Association among cardiorespiratory fitness, plasma biomarkers of pathology and astrocyte reactivity, and cognition in autosomal-dominant Alzheimer's disease. - Guzmán-Vélez, Edmarie; Aguillón, David; Rivera-Hernández, Angelys; Baena, Ana Y; Londoño-Sotomayor, Natalia; Picard, Glen; Kramer, Arthur F; Arnold, Steven E; Caraballo-Gracia, Domingo I; Taylor, J Andrew; Quiroz, Yakeel T (J Alzheimers Dis, 2025)
BackgroundHigh cardiorespiratory fitness has been associated with greater neuroplasticity, and slower neurodegeneration and cognitive decline in healthy adults. Yet, less is known about whether low-to-intermediate cardiorespiratory fitness is associated with lower markers of disease progression in the preclinical stage of Alzheimer's disease (AD).ObjectiveWe investigated whether cardiorespiratory fitness was associated with plasma biomarkers for AD-related pathology, neural injury and astrocyte reactivity, and episodic memory in Presenilin-1 E280A carriers without dementia from the world's largest kindred with autosomal-dominant AD.MethodsTwenty-seven mutation carriers (25 cognitively unimpaired, 2 with mild cognitive impairment; ages: μ=30.22 years, SD = 5.24; 74% female) participated in the study. Participants underwent a graded aerobic fitness test to assess cardiorespiratory fitness, measured in maximum metabolic equivalent of task (MET). Plasma biomarkers included amyloid 42/40, phosphorylated tau-181, neurofilament light chain, and glial fibrillary acidic protein. Participants completed the Consortium to Establish a Registry for AD word list learning and delayed recall. We conducted multiple linear regressions controlling for age, sex, and years of education.ResultsFourteen participants' MET values were indicative of low cardiorespiratory fitness (< MET), and 13 participants' MET values of intermediate cardiorespiratory fitness (9-14 MET). METs were not associated with age, biomarkers, or episodic memory.ConclusionsOur findings suggest that low-to-intermediate cardiorespiratory fitness may not be associated with biomarkers for AD-related pathology, neural injury and astrocyte reactivity, or memory in people at genetic risk for dementia. Longitudinal studies and randomized-controlled trials are needed to better understand the relationships among cardiorespiratory fitness and AD progression.

Baseline associations of office and ambulatory blood pressure monitoring with cognitive function and dementia prevalence. - Melgarejo, Jesus D; Patil, Dhrumil; Charisis, Sokratis; Vatcheva, Kristina P; Mejia-Arango, Silvia; Mena, Luis J; Satizabal, Claudia L; Gaona, Ciro; Silva, Egle; Manusov, Eron; Lee, Joseph H; Terwilliger, Joseph D; et al. (J Alzheimers Dis, 2025)
BackgroundHigh blood pressure has been associated with dementia prevalence and incident. However, it is unclear the relationship of office and ambulatory BP monitoring with cognitive function and dementia and in particular, it remains unknown whether ambulatory BP variability relates to dementia.ObjectiveTo investigate the associations of office and 24-h blood pressure (BP) with cognitive function and dementia prevalence.MethodsCross-sectional population-based study of 1435 participants aged ≥40 years with office BP/24-h BP, and cognitive assessments (Mini-Mental State Examination [MMSE] and Selective Reminding Test [SRT]). Dementia was diagnosed with a clinical dementia rating ≥1.0. Statistics included logistic and linear regression models.ResultsThe mean age was 63.8 ± 10.3 years old and 995 (69.3%) were women. Out of the 1435 participants, 46 (3.20%) had dementia at baseline. Office and 24-h BP levels were not associated with dementia but with one SRT. Increasing 24-h systolic BP variability was associated with lower MMSE (adjusted mean, -0.08; 95% confidence interval [CI], -0.13, -0.03), and SRT (adjusted means ranged from -0.13 to -0.06; 95% CI ranging from -0.19 to -0.01) scores and 1.48-fold greater odds of dementia (95% CI, 1.09-2.02) regardless of BP level.ConclusionsElevated 24-h BP variability, not the BP level, seems to have a stronger association with lower cognitive function and dementia prevalence. Prospective studies are needed to address whether 24-h BP variability relates to cognitive decline and dementia incidence.

Cost-effectiveness of diagnosing and treating patients with early Alzheimer's disease with anti-amyloid treatment in a clinical setting. - Wimo, Anders; Handels, Ron; Blennow, Kaj; Kirsebom, K Bjørn-Eivind; Selnes, Per; Bon, Jaka; Emersic, Andreja; Gonzalez-Ortiz, Fernando; Gregoric Kramberger, Milica; Sköldunger, Anders; Speh, Andreja; Timón-Reina, Santiago; et al. (J Alzheimers Dis, 2025)
BackgroundThe introduction of anti-amyloid treatments (AAT) for Alzheimer's disease (AD) has put the cost-effectiveness into focus.ObjectiveEstimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD.MethodsDiagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5000/year), infusions and monitoring.ResultsCompared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration.ConclusionsCompared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.

Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion, but no amyloid binding. - Starmans, Naomi Lp; Leeuwis, Anna E; Bennink, Edwin; Meyer Viol, Sebastiaan L; Golla, Sandeep Sv; Dankbaar, Jan Willem; Bron, Esther E; Biessels, Geert Jan; Kappelle, L Jaap; van der Flier, Wiesje M; Tolboom, Nelleke (J Alzheimers Dis, 2025)
BackgroundCarotid occlusive disease is a risk factor for cognitive decline. A possible underlying etiology is that hemodynamic impairment results in decreased cerebral perfusion, exacerbated amyloid-β accumulation (Aβ) and poorer cognitive performance.ObjectiveWe aimed to determine whether patients with unilateral internal carotid artery (ICA) occlusion have less cerebral perfusion and more Aβ in the ipsilateral than in the contralateral hemisphere, and whether perfusion and Aβ are associated with cognitive functioning.MethodsWe included 20 patients (age 67.2 ± 7.0 years, 8 females, MMSE 29 [27-29]) with unilateral ICA occlusion, which underwent neuropsychological assessment and dynamic F-Florbetaben positron emission tomography (PET). Global and regional relative perfusion (R) and binding potential (BP) were obtained from the PET-images using a simplified reference tissue model. We performed Wilcoxon signed-rank tests to examine differences between hemispheres within subjects and linear regression to investigate associations with cognitive functioning.ResultsMedian global R was 0.911 (0.883-0.950) and global BP was 0.172 (0.129-0.187). R was lower in the hemisphere ipsilateral to the ICA occlusion than in the contralateral hemisphere (0.899 [0.876-0.921] versus 0.935 [0.889-0.970]). BP did not differ significantly between hemispheres (ipsilateral 0.172 [0.124-0.181] versus contralateral 0.168 [0.137-0.191]). Neither cerebral perfusion nor Aβ burden were associated with cognitive functioning.ConclusionsPatients with unilateral ICA occlusion did not have more Aβ in the ipsilateral hemisphere than in the contralateral hemisphere despite ipsilateral hypoperfusion. Perfusion and Aβ were unrelated to cognitive functioning. This indicates that cognitive impairment in patients with ICA occlusion is not due to exacerbated Aβ accumulation.

Factors associated with a healthy diet and willingness to change dietary behavior in older adults at increased risk of dementia. - Blotenberg, Iris; Zülke, Andrea E; Luppa, Melanie; Wittmann, Felix; Fankhänel, Thomas; Weise, Solveig; Döhring, Juliane; Escales, Catharina; Kosilek, Robert P; Michel, Irina; Brettschneider, Christian; Oey, Anke; et al. (J Alzheimers Dis, 2025)
BackgroundHealthy dietary patterns have been linked to reduced risks for cardiovascular diseases and dementia, making nutrition an essential part of a comprehensive approach for dementia prevention. Knowledge about factors associated with a healthy diet in people with increased dementia risk is scarce.ObjectiveTo analyze dietary habits and associated factors in older adults with increased dementia risk in Germany.MethodsWe used baseline-data of the AgeWell.de-trial (n = 1001, %= 52.2, M= 69.0, SD = 4.9). Nutrition was assessed using a composite score, comprising 11 components covered by national recommendations for a healthy diet (range = 0-11 points). Linear regressions assessed associations of sociodemographic, social, health-related and psychological factors with consumption of a healthy diet. Further, we assessed stages of change based on the transtheoretical model of behavior change.ResultsConsumption of a healthy diet was moderate (Median = 4, IQR = 2). Female sex (b = 0.64, 95% CI: 0.41, 0.88), higher levels of motivation for healthy eating (b = 0.22, 95% CI: 0.10, 0.34) and higher self-efficacy (b = 0.33, 95% CI: 0.20, 0.46) were linked to a healthy diet. Regarding the stages of behavior change, the majority were in the maintenance stage (45.2%), followed by the contemplation (21.5%) and precontemplation (21.2%) stages.ConclusionsResults suggest room for improvement regarding a healthy diet in our sample. Lifestyle-based interventions in older adults should be tailored towards current levels of motivation and self-efficacy of participants. Including modules targeting motivation and self-efficacy might help maximize intervention effectiveness.

Increased risk of dementia associated with herpes simplex virus infections: Evidence from a retrospective cohort study using U.S. electronic health records. - Araya, Katherine; Watson, Riley; Khanipov, Kamil; Golovko, George; Taglialatela, Giulio (J Alzheimers Dis, 2025)
BACKGROUND: Alzheimer's disease is the most common age-related dementia. Recent compelling evidence from previous retrospective electronic health record (EHRs) studies suggests that herpes simplex virus (HSV) infections may be a risk factor for developing dementia. However, no age and propensity score matched studies have been published in a United States general population cohort study to date. OBJECTIVE: We aimed to identify whether HSV infection shows a significantly increased risk of the development of dementia in a sizable and heterogeneous cohort. We investigated whether herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), or coinfections with both serotypes pose a greater risk of developing dementia across different biological sexes and racial groups. METHODS: EHRs from patients with a history of HSV or specific serotypes (HSV1 or HSV2) infection were selected for analysis. These records were compared to a propensity-matched control group and analyzed for hazard and odds ratios through TriNetX. RESULTS: There was a significant difference in dementia incidence in the HSV-infected group versus the control. Individuals with a history of HSV, HSV1, HSV2, and coinfection all showed a significant risk of developing dementia compared to controls. Males with HSV2 are at a higher risk of dementia outcome than females with HSV2. CONCLUSIONS: While consistent with previous reports, these findings are the first to establish a higher risk of developing dementia in patients who have any HSV diagnosis using a nationwide, population-based matched cohort study in the United States.

Leptin, adiponectin, body mass index, and incident cognitive impairment. - Thacker, Evan L; Karki, Reena; Gabor, Rachel; Blades, Natalie J; Sawyer, Russell P; Kouambo Beckodro, Cyrille N; Preece, Quinn; Prince, Samuel; Smith, McKay M; Gillett, Sarah R; Judd, Suzanne E; Kennedy, Richard E; et al. (J Alzheimers Dis, 2025)
BackgroundDisordered metabolism affects risk for cognitive decline, Alzheimer's disease, and other dementias, likely through pathways involving adipokines.ObjectiveAnalyze incident cognitive impairment in relation to leptin, adiponectin, body mass index, and other risk factors.MethodsNested case-control study within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort of 30,239 adults in the US. Cases with incident cognitive impairment (n = 489) scored >1.57 SD below demographically adjusted means on ≥2 of 3 cognitive tests: word list learning, word list delayed recall, and category fluency. Cognitively intact controls (n = 583) were randomly selected within demographic strata. Leptin and adiponectin were assayed in thawed blood that had been stored at baseline.ResultsIn participants with normal weight, lower leptin was associated with higher odds of cognitive impairment. Relative to leptin = 25 ng/mL, adjusted ORs were 1.5 (95% CI: 1.2, 1.9) at leptin = 15 ng/mL, 0.8 (0.8, 0.9) at leptin = 30 ng/mL, and 0.5 (0.4, 0.8) at leptin = 45 ng/mL. In participants with obesity, higher adiponectin was associated with higher odds of cognitive impairment. Relative to adiponectin = 25 ng/mL, adjusted ORs were 0.8 (95% CI: 0.7, 1.0) at adiponectin = 15 ng/mL, 1.1 (1.0, 1.2) at adiponectin = 30 ng/mL, and 1.3 (1.0, 1.7) at adiponectin = 45 ng/mL. Associations of adipokines with cognitive impairment varied across levels of other risk factors.ConclusionsAdipokines, in concert with body mass index, play complex roles in cognitive health, with many avenues open for further investigation.

Lipopolysaccharides from indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer's disease. - Gui, Shuge; Zeng, Fan; Wu, Zhou; Nonaka, Saori; Sano, Tomomi; Ni, Junjun; Nakanishi, Hiroshi; Moriyama, Masafumi; Kanematsu, Takashi (J Alzheimers Dis, 2025)
BackgroundLipopolysaccharides from s (LPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of LPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that LPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with LPS (0.1 μg/mL), soluble Aβ (0.1 μM) or AL (combined LPS and soluble Aβ at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ, LPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APP mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that LPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.

Medications and cognitive decline in Alzheimer's disease: Cohort cluster analysis of 15,428 patients. - Grau-Jurado, Pol; Mostafaei, Shayan; Xu, Hong; Mo, Minjia; Petek, Bojana; Kalar, Irena; Naia, Luana; Kele, Julianna; Maioli, Silvia; Pereira, Joana B; Eriksdotter, Maria; Chatterjee, Saikat; et al. (J Alzheimers Dis, 2025)
BACKGROUND: Medications for comorbid conditions may affect cognition in Alzheimer's disease (AD). OBJECTIVE: To explore the association between common medications and cognition, measured with the Mini-Mental State Examination. METHODS: Cohort study including persons with AD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem). Medications were included if they were used by ≥5% of patients (26 individual drugs). Each follow-up was analyzed independently by performing 100 Monte-Carlo simulations of two steps each 1) k-means clustering of patients according to Mini-Mental State Examination at follow-up and its decline since previous measure, and 2) Identification of medications presenting statistically significant differences in the proportion of users in the different clusters. RESULTS: 15,428 patients (60.38% women) were studied. Four clusters were identified. Medications associated with the best cognition cluster (relative to the worse) were atorvastatin (point estimate 1.44 95% confidence interval [1.15-1.83] at first follow-up, simvastatin (1.41 [1.11-1.78] at second follow-up), warfarin (1.56 [1.22-2.01] first follow-up), zopiclone (1.35 [1.15-1.58], and metformin (2.08 [1.35-3.33] second follow-up. Oxazepam (0.60 [0.50-0.73] first follow-up), paracetamol (0.83 [0.73-0.95] first follow-up), cyanocobalamin, felodipine and furosemide were associated with the worst cluster. Cholinesterase inhibitors were associated with the best cognition clusters, whereas memantine appeared in the worse cognition clusters, consistent with its indication in moderate to severe dementia. CONCLUSIONS: We performed unsupervised clustering to classify patients based on their current cognition and cognitive decline from previous testing. Atorvastatin, simvastatin, warfarin, metformin, and zopiclone presented a positive and statistically significant associations with cognition, while oxazepam, cyanocobalamin, felodipine, furosemide and paracetamol, were associated with the worst cluster.

Performance of a smell identification test versus the Mini-Mental Status Exam for the detection of dementia and cognitive impairment among persons with cognitive concerns in primary care. - Luchsinger, Jose A; Teresi, Jeanne A; Valdez, Lenfis; Rosario, Dahiana; de Miguel, Maria; Taylor, Delphine; Singer, Jessica; Chang, Nancy; Fuller, William S; Boquín, Cyrus; Silver, Stephanie; Eimicke, Joseph P; et al. (J Alzheimers Dis, 2025)
BackgroundOdor identification deficits predict Alzheimer's disease (AD) in epidemiological studies.ObjectiveTo compare the accuracy of a short odor identification test with a short cognitive screening test for the detection of dementia and cognitive impairment in elderly persons with cognitive concerns.MethodsThis was a cross-sectional study of 600 participants 65 years and older, without known mild cognitive impairment (MCI) or dementia, with cognitive concerns, attending primary care practices in New York City. The odor identification test was the Brief Smell Identification Test (BSIT). The comparator test was the Mini Mental Status Exam II (MMSE). Cognitive diagnoses were made using the National Alzheimer's Coordinating Center Uniform Data set (NACC-UDS) version 3 forms with slight modifications. Test performance was compared using Receiver Operating Characteristic analyses.ResultsThe mean age was 72.65 ± 6.31 years, 73.3% were female, 63.3% were Hispanic, 13.5% non-Hispanic Black, and 20.8% non-Hispanic White; 23.5% were classified as normal cognition, 27.7% as cognitive impairment-not mild cognitive impairment (MCI), 31.2% as amnestic MCI, 5.7% as non-amnestic MCI, and 12% as dementia. The MMSE was superior to the BSIT in detecting dementia and any cognitive impairment. Combining abnormal scores in the BSIT (≤8) to MMSE (≤24) improved the MMSE's specificity and positive predictive value (PPV) in detecting cognitive impairment.ConclusionsThe MMSE was superior to the BSIT in detecting dementia and cognitive impairment in primary care but using both tests improved specificity and PPV for identifying persons with subjective complaints needing further cognitive and biomarker evaluation.

The potential impact of optimal blood pressure treatment intensity to reduce disparities in dementia between Black and White individuals. - Levine, Deborah A; Sussman, Jeremy B; Hayward, Rodney A; Gałecki, Andrzej T; Whitney, Rachael T; Briceño, Emily M; Gross, Alden L; Giordani, Bruno J; Elkind, Mitchell Sv; Gottesman, Rebecca F; Gaskin, Darrell J; Sidney, Stephen; et al. (J Alzheimers Dis, 2025)
BACKGROUND: Black adults have higher dementia risk than White adults. Whether tighter population-level blood pressure (BP) control reduces this disparity is unknown. OBJECTIVE: Estimate the impact of optimal BP treatment intensity on racial disparities in dementia. METHODS: A microsimulation study of US adults ≥18 across a life-time policy-planning horizon. BP treatment strategies were the Systolic Blood Pressure Intervention Trial (SPRINT) protocol, the Eighth Joint National Committee (JNC-8) recommendations, and usual care (non-intervention control). Outcomes were all-cause dementia, atherosclerotic cardiovascular disease (ASCVD), stroke, myocardial infarction, non-ASCVD death, global cognitive performance, and optimal brain health (being free of dementia, cognitive impairment, or stroke). Population-level and individual-level effects stratified by race were estimated. RESULTS: Optimal population-level implementation of a SPRINT-based BP treatment strategy, compared to usual care, would average annual dementia incidence in White, but not Black, adults (1% versus 0%), due to hypertensive individuals' greater survival, and reduce annual ASCVD events more in Black than White adults (13% versus 5%). Under a SPRINT-based strategy, individuals with hypertension gained more years lived without dementia, ASCVD, myocardial infarction, or stroke and more years lived in optimal brain health. A SPRINT-based strategy did not attenuate individual-level race disparities in outcomes, except stroke. Due to longer life expectancy, a SPRINT-based strategy did not substantially reduce lifetime dementia risk in either group. The JNC-8-based strategy had similar but smaller effects as the SPRINT-based strategy. CONCLUSIONS: Our results suggest that tighter population-level BP control would not reduce population-level disparities in dementia between US Black and White adults.

African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer's Disease Measured by pTau181. - Rajabli, Farid; Seixas, Azizi A; Akgun, Bilcag; Adams, Larry D; Inciute, Jovita; Hamilton, Kara L; Whithead, Patrice G; Konidari, Ioanna; Gu, Tianjie; Arvizu, Jamie; Golightly, Charles G; Starks, Takiyah D; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Cognitive and functional abilities in individuals with Alzheimer's disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP. While cognitive and functional impairments are correlated, they are distinguishable in their manifestations. OBJECTIVE: To investigate whether levels of education are associated with functional impairments among those with ADP. METHODS: This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels. RESULTS: The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W = 730.5, p = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W = 555.5, p = 0.022). CONCLUSION: This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4.
Keywords: Alzheimer Disease; Apolipoprotein E4; Cognitive Dysfunction; Educational Status; Humans; Resilience, Psychological

Amnestic Syndrome in Memory Clinics: Similar Morphological Brain Patterns in Older Adults with and without Alzheimer's Disease. - Lalive, Hadrien M; Griffa, Alessandra; Carlier, Sabrina; Nasuti, Mirco; Di Noto, Tommaso; Maréchal, Bénédicte; Rouaud, Olivier; Allali, Gilles (J Alzheimers Dis, 2024)
BACKGROUND: Amnestic syndrome of the hippocampal type (ASHT) in Memory Clinics is a presentation common to Alzheimer's disease (AD). However, ASHT can be found in other neurodegenerative disorders. OBJECTIVE: To compare brain morphometry including hippocampal volumes between amnestic older adults with and without AD pathology and investigate their relationship with memory performance and cerebrospinal fluid (CSF) biomarkers. METHODS: Brain morphometry of 92 consecutive patients (72.5±6.8 years old; 39% female) with Free and Cued Selective Recall Reminding Test (FCSRT) total recall < 40/48 was assessed with an automated algorithm and compared between AD and non-AD patients, as defined by CSF biomarkers. RESULTS: AD and non-AD patients presented comparable brain morphology. Total recall was associated to hippocampal volume irrespectively from AD pathology. CONCLUSIONS: Brain morphometry, including hippocampal volumes, is similar between AD and non-AD older adults with ASHT evaluated in a Memory Clinic, underlying the importance of using molecular biomarkers for the diagnosis of AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Biomarkers; Brain; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mental Recall; Neuropsychological Tests; Organ Size

The Association Between Neuropathological Lesions and Body Mass Index Is Independent of Cognitive Abilities. - Ururahy, Raul Dos Reis; do Val, Marina Scott; Ciciliati, Aline Maria Macagnan; Leite, Renata Elaine Paraizo; Paes, Vitor Ribeiro; Rodrigues, Roberta Diehl; Grinberg, Lea Tenenholz; Pasqualucci, Carlos Augusto; Jacob Filho, Wilson; Suemoto, Claudia Kimie (J Alzheimers Dis, 2024)
BACKGROUND: The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes. OBJECTIVE: We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association. METHODS: In 1,170 participants, sociodemographic data, clinical history, and cognitive post-mortem evaluation were assessed with an informant. Neuropathological evaluation was performed in all cases. Linear regression models were used to investigate the association between neuropathological lesions (exposure variable) and BMI (outcome) adjusted for demographic, clinical, and cognitive variables in the whole sample, and in only those with normal cognition. Corrections for multiple comparisons were performed. In addition, a mediation analysis was performed to investigate the direct and indirect effects of cognitive abilities on the association between neuropathology and BMI. RESULTS: Individuals with lower BMI had a higher burden of neuropathological lesions and poorer cognitive abilities. Only neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI, while other neurodegenerative and cerebrovascular lesions were not. NFT were indirectly associated with BMI through cognitive abilities, and also directly, even in participants with normal cognition. CONCLUSIONS: Neurofibrillary tangles were directly associated with low BMI even in individuals with preclinical Alzheimer's disease.

Association of Plasma Amyloid-β and Dementia Among Black and White Older Adults. - Jiang, Xiaqing; Bahorik, Amber L; Graff-Radford, Neill R; Yaffe, Kristine (J Alzheimers Dis, 2024)
BACKGROUND: Plasma amyloid-β (Aβ) has emerged as an important tool to detect risks of Alzheimer's disease and related dementias, although research in diverse populations is lacking. OBJECTIVE: We compared plasma Aβ 42/40 by race with dementia risk over 15 years among Black and White older adults. METHODS: In a prospective cohort of 997 dementia-free participants (mean age 74±2.9 years, 55% women, 54% Black), incident dementia was identified based on hospital records, medication, and neurocognitive test over 15 years. Plasma Aβ 42/40 was measured at Year 2 and categorized into low, medium, and high tertile. We used linear regression to estimate mean Aβ 42/40 by race and race-stratified Cox proportional hazards models to assess the association between Aβ 42/40 tertile and dementia risk. RESULTS: Black participants had a lower age-adjusted mean Aβ 42/40 compared to White participants, primarily among APOE ɛ4 non-carriers (Black: 0.176, White: 0.185, p = 0.035). Among Black participants, lower Aβ 42/40 was associated with increased dementia risk: 33% in low (hazard ratios [HR] = 1.77, 95% confidence interval 1.09-2.88) and 27% in medium tertile (HR = 1.67, 1.01-2.78) compared with 18% in high Aβ 42/40 tertile; Increased risks were attenuated among White participants: 21% in low (HR = 1.43, 0.81-2.53) and 23% in medium tertile (HR = 1.27, 0.68-2.36) compared with 15% in high Aβ 42/40 tertile. The interaction by race was not statistically significant. CONCLUSIONS: Among community-dwelling, non-demented older adults, especially APOE ɛ4 non-carriers, Black individuals had lower plasma Aβ 42/40 and demonstrated a higher dementia risk with low Aβ 42/40 compared with White individuals.

Association of Statin Use with Dementia Risk Among Older Adults in Japan: A Nested Case-Control Study Using the LIFE Study. - Ge, Sanyu; Kitamura, Tetsuhisa; Zha, Ling; Komatsu, Masayo; Komukai, Sho; Murata, Fumiko; Maeda, Megumi; Gon, Yasufumi; Kimura, Yasuyoshi; Kiyohara, Kosuke; Sobue, Tomotaka; Fukuda, Haruhisa (J Alzheimers Dis, 2024)
BACKGROUND: Previous studies have shown a possible association between statin use and a decreased risk of dementia, but the association has not been sufficiently established, especially in the super-aging society of Japan. OBJECTIVE: This study aimed to determine the association between statin use and the risk of dementia among Japanese participants aged> =65 years old. METHODS: Data from the Longevity Improvement and Fair Evidence (LIFE) Study were utilized, including medical and long-term care (LTC) claim data from 17 municipalities between April 2014 and December 2020. A nested case-control study was conducted with one case matched to five controls based on age, sex, municipality, and year of cohort entry. We used a conditional logistic regression model to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: This study included 57,302 cases and 283,525 controls, with 59.7% of the participants being woman. After adjusting for potential confounders, statin use was associated with a lower risk of dementia (OR, 0.70; 95% CI: 0.68-0.73) and Alzheimer's disease (OR: 0.66; 95% CI: 0.63-0.69). Compared with non-users, the ORs of dementia were as follows: 1.42 (1.34-1.50) for 1-30 total standardized daily dose (TSDD), 0.91 (0.85-0.98) for 31-90 TSDD, 0.63 (0.58-0.69) for 91-180 TSDD, and 0.33 (0.31-0.36) for >180 TSDD in dose-analysis. CONCLUSIONS: Statin use is associated with a reduced risk of dementia and Alzheimer's disease among older Japanese adults. A low cumulative statin dose is associated with an increased risk of dementia, whereas a high cumulative statin dose is a protective factor against dementia.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Dementia; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Risk Factors

Associations of Physical Activity Engagement with Cerebral Amyloid-β and Tau from Midlife. - Gonzales, Mitzi M; Kojis, Daniel; Spartano, Nicole L; Thibault, Emma G; DeCarli, Charles S; El Fakhri, Georges; Johnson, Keith A; Beiser, Alexa S; Seshadri, Sudha (J Alzheimers Dis, 2024)
BACKGROUND: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. OBJECTIVE: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. METHODS: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. RESULTS: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = -0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = -0.035(0.009), p = 0.001), inferior temporal (β (SE) = -0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = -0.033(0.010), p = 0.002). CONCLUSIONS: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities.

Blood-Based mtDNA Quantification Indicates Population-Specific Differences Associated with Alzheimer's Disease-Related Risk. - Gorham, Isabelle K; Reid, Danielle Marie; Sun, Jie; Zhou, Zhengyang; Barber, Robert C; Phillips, Nicole R (J Alzheimers Dis, 2024)
BACKGROUND: Age is known to be the biggest risk factor for Alzheimer's disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. OBJECTIVE: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. METHODS: Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, MA n = 284, NHW n = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. RESULTS: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOEɛ2/ɛ3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. CONCLUSIONS: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk.

A Brief History of the Progress in Our Understanding of Genetics and Lifestyle, Especially Diet, in the Risk of Alzheimer's Disease. - Grant, William B (J Alzheimers Dis, 2024)
The two major determining factors for Alzheimer's disease (AD) are genetics and lifestyle. Alleles of the apolipoprotein E (APOE) gene play important roles in the development of late-onset AD, with APOEɛ4 increasing risk, APOEɛ3 being neutral, and APOEɛ2 reducing risk. Several modifiable lifestyle factors have been studied in terms of how they can modify the risk of AD. Among these factors are dietary pattern, nutritional supplements such as omega-3 fatty acids, and B vitamins, physical exercise, and obesity, and vitamin D. The Western diet increases risk of AD, while dietary patterns such as the Mediterranean and vegetarian/vegan diets reduce risk. Foods associated with reduced risk include coffee, fruits and vegetables, whole grains and legumes, and fish, while meat and ultraprocessed foods are associated with increased risk, especially when they lead to obesity. In multi-country ecological studies, the amount of meat in the national diet has the highest correlation with risk of AD. The history of research regarding dietary patterns on risk of AD is emphasized in this review. The risk of AD can be modified starting at least by mid-life. People with greater genetic risk for AD would benefit more by choosing lifestyle factors to reduce and/or delay incidence of AD.
Keywords: Alzheimer Disease; Apolipoproteins E; Diet; Genetic Predisposition to Disease; Humans; Life Style; Risk Factors

Cerebrospinal Fluid Proteomics Identifies Potential Biomarkers for Early-Onset Alzheimer's Disease. - Li, Dazhi; Xie, Qiang; Xie, Jikui; Ni, Ming; Wang, Jinliang; Gao, Yuru; Wang, Yaxin; Tang, Qiqiang (J Alzheimers Dis, 2024)
BACKGROUND: Early-onset Alzheimer's disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer's disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. OBJECTIVE: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. METHODS: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. RESULTS: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results. CONCLUSIONS: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins.

Cognitive Outcomes in Autosomal-Dominant Alzheimer's Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation. - Giudicessi, Averi; McDowell, Celina Pluim; Martinez, Jairo E; Baena, Ana; Vila-Castelar, Clara; Norton, Daniel; Aguirre-Acevedo, Daniel C; Tirado, Victoria; Bocanegra, Yamile; Guzmán-Vélez, Edmarie; Lopera, Francisco; Cronin-Golomb, Alice; et al. (J Alzheimers Dis, 2024)
BACKGROUND: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. OBJECTIVE: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. METHODS: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. RESULTS: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. CONCLUSIONS: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

Combined Neuroinflammation and Amyloid PET Markers in Predicting Disease Progression in Cognitively Impaired Subjects. - Leng, Fangda; Hinz, Rainer; Gentleman, Steve; Dani, Melanie; Brooks, David J; Edison, Paul (J Alzheimers Dis, 2024)
BACKGROUND: Neuroinflammation in Alzheimer's disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. OBJECTIVE: The current study aims to interrogate the predictive value of neuroinflammation biomarker (11C-PBR28 PET), together with A/T/N imaging markers on disease deterioration in a cognitively impaired patient cohort. METHODS: The study included 6 AD and 27 MCI patients, who had MRI, 11C-PBR28, 18F-flutemetamol (amyloid marker), 18F-AV1451 (tau marker) PET scans, and were followed up with multiple neuropsychological assessments for at least one year (1.6 and 2.8 years on average for AD and MCI). The predictive values of imaging biomarkers on baseline and longitudinal cognition were interrogated using linear regression to identify the biomarkers that could explain disease progression. RESULTS: Linear mixed models found the average intercepts (baseline) MMSE were 23.5 for AD and 28.2 for MCI patients, and the slope of MMSE (annual change) were -0.74 for AD and -0.52 for MCI patients. White matter microstructural integrity was predictive of baseline cognition, while PET markers of amyloid, tau and neuroinflammation were predictive of longitudinal cognitive decline. Both amyloid and neuroinflammation PET markers were predictors independent of each other. And a sub-group analysis showed the predictive effect of neuroinflammation on cognitive decline is independent of amyloid and tau. CONCLUSIONS: Our study highlights the prognostic value of disease specific markers (amyloid, tau and neuroinflammation) in clinically diagnosed AD and MCI patients and suggests that the effects of these molecular markers are mediated by structural damage to the brain.

Comparative accuracy of Mini-Linguistic State Examination, Addenbrooke's Cognitive Examination, and Depistage Cognitif de Quebec for the diagnosis of primary progressive aphasia. - Fernández-Romero, Lucía; Morello-García, Florentina; Laforce, Robert; Delgado-Alonso, Cristina; Delgado-Álvarez, Alfonso; Gil-Moreno, María José; Lavoie, Monica; Matías-Guiu, Jorge; Cuetos, Fernando; Matías-Guiu, Jordi A (J Alzheimers Dis, 2024)
BACKGROUND: Clinical diagnosis in primary progressive aphasia (PPA) is challenging. Recently, emphasis has been placed on the importance of screening evaluation. Three different screening tests that use different strategies based on the assessment of language (Mini-Linguistic State Examination, MLSE) or different cognitive domains (Addenbrooke's Cognitive Examination, ACE-III and Dépistage Cognitif de Québec, DCQ) have been proposed and independently validated. These tests aim to detect PPA and classify into the three main variants (non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA)). OBJECTIVE: This study aims to evaluate and compare the diagnostic capacity of these three instruments in PPA. METHODS: A cross-sectional study including 43 patients with PPA (nfvPPA ( = 19), svPPA ( = 8), and lvPPA ( = 16)) and 21 cognitively unimpaired controls was conducted. Clinical diagnoses were established based on an extensive multidisciplinary assessment including neuropsychological assessment, fluorodeoxyglucose-positron emission tomography, MRI, and cerebrospinal fluid biomarkers. Both PPA patients and controls completed the three tests (MLSE, ACE-III, and DCQ). RESULTS: Internal consistency was excellent for the three tests. The area under the curve for the diagnosis of PPA was 0.950 for MLSE, 0.953 for ACE-III, and 0.933 for DCQ. Correlations between the three tests were high. The MLSE, ACE-III, and DCQ tests obtained adequate levels of discrimination between the variants of PPA, with accuracies between 76-79%. CONCLUSIONS: This study confirms the validity of ACE-III, MLSE, and DCQ for the diagnosis of PPA and its variants. This suggests that detailed assessment of linguistic characteristics (MLSE) and non-linguistic features (DCQ, ACE-III) are relevant for the diagnosis and classification of PPA.
Keywords: Aged; Aphasia, Primary Progressive; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Reproducibility of Results

Creating an Unprotected Class: Addressing Legal Risks in the Era of Biologically-Defined Alzheimer's Disease. - Vaishnav, Neil; Gonzalez, Rosa; Karunungan, Krystal; Tyler, Ana; Zheng, William; Arias, Jalayne J (J Alzheimers Dis, 2024)
BACKGROUND: Documentation of preclinical biomarker tests for Alzheimer's disease (AD) in the medical record may expose patients to employment and insurance discrimination risks. There is a gap in research describing clinicians' approaches to documenting biomarker results. OBJECTIVE: To evaluate discrimination risks faced by patients undergoing biomarker testing for AD through a qualitative analysis of clinician documentation practices. METHODS: Semi-structured interviews using hypothetical patient scenarios. The qualitative analysis focused on interviewees' responses related to documentation and disclosure of results. RESULTS: We collected and analyzed 17 interviews with dementia experts; and identified three approaches to documenting biomarkers as: an association with active AD, noninformative, and an increased susceptibility for AD. Those who associated biomarkers with active disease were more likely to favor disclosure to employers and insurers, which could increase discrimination risks. CONCLUSIONS: This study demonstrates the variety of documentation and disclosure practices likely to emerge for preclinical AD biomarker tests and highlights a need for guidelines in this area.
Keywords: Alzheimer Disease; Biomarkers; Disclosure; Humans

Dementia Ideal Care: Ecosystem Map of Best Practices and Care Pathways Enhanced by Technology and Community. - Dombrowski, Wen; Mims, Adrienne; Kremer, Ian; Cano Desandes, Pedro; Rodrigo-Herrero, Silvia; Epps, Fayron; Snow, Teepa; Gutierrez, Myrna; Nasta, Anil; Epperly, Mikele Bunce; Manaloto, Katrina; Hansen, Jennie Chin (J Alzheimers Dis, 2024)
BACKGROUND: Globally, much work has been done by nonprofit, private, and academic groups to develop best practices for the care of people living with dementia (PLWD), including Alzheimer's disease. However, these best practices reside in disparate repositories and tend to focus on one phase of the patient journey or one relevant group. OBJECTIVE: To fill this gap, we developed a Dementia Ideal Care Map that everyone in the dementia ecosystem can use as an actionable tool for awareness, policy development, funding, research, training, service delivery, and technology design. The intended audience includes (and not limited to) policymakers, academia, industry, technology developers, health system leaders, clinicians, social service providers, patient advocates, PLWD, their families, and communities at large. METHODS: A search was conducted for published dementia care best practices and quality measures, which were then summarized in a visual diagram. The draft diagram was analyzed to identify barriers to ideal care. Then, additional processes, services, technologies, and quality measures to overcome those challenges were brainstormed. Feedback was then obtained from experts. RESULTS: The Dementia Ideal Care Map summarizes the ecosystem of over 200 best practices, nearly 100 technology enablers, other infrastructure, and enhanced care pathways in one comprehensive diagram. It includes psychosocial interventions, care partner support, community-based organizations; awareness, risk reduction; initial detection, diagnosis, ongoing medical care; governments, payers, health systems, businesses, data, research, and training. CONCLUSIONS: Dementia Ideal Care Map is a practical tool for planning and coordinating dementia care. This visualized ecosystem approach can be applied to other conditions.
Keywords: Delivery of Health Care; Dementia; Humans; Practice Guidelines as Topic

Early Astrocytic Dysfunction Is Associated with Mistuned Synapses as well as Anxiety and Depressive-Like Behavior in the AppNL-F Mouse Model of Alzheimer's Disease. - Portal, Benjamin; Södergren, Moa; Parés I Borrell, Teo; Giraud, Romain; Metzendorf, Nicole G; Hultqvist, Greta; Nilsson, Per; Lindskog, Maria (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD. OBJECTIVE: We aimed to characterize early synaptic impairments in the AppNL-F knock-in mouse model of AD, especially to understand the contribution of astrocytes to early brain dysfunctions. METHODS: The AppNL-F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-β plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior. RESULTS: Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg). CONCLUSIONS: We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms.

The Effects of Pomegranate Seed Oil on Mild Cognitive Impairment. - Chatzikostopoulos, Thanos; Gialaouzidis, Moses; Koutoupa, Anna; Tsolaki, Magda (J Alzheimers Dis, 2024)
BACKGROUND: In recent years, there has been a growing interest, supported by many experimental and clinical studies, about the benefits of pomegranate in preventing various pathologic conditions, including brain neurodegeneration. The pomegranate seed oil (PSO) contains high levels of fatty acids that have antioxidant and anti-inflammatory properties. OBJECTIVE: Due to the lack of clinical trials, the aim of the present study was to investigate the effects of PSO on cognition of people with mild cognitive impairment (MCI). METHODS: Eighty people with the diagnosis of MCI were randomized forty to take 5 drops of PSO and follow the Mediterranean Diet (MeDi) and forty just followed MeDi. All were examined with an extensive neuropsychological assessment before and after one year of treatment. RESULTS: The results showed that the participants who took the PSO had statistically significantly better global cognition (p = 0.004), verbal episodic memory (p = 0.009), and processing and executive functions (p < 0.001) in contrast with the participants who did not take it. CONCLUSIONS: In conclusion, the PSO can be beneficial for people with MCI as it is helpful for some important cognitive domains. As PSO is a natural product that does not burden the human body, it can be used by people with MCI and be a significant and promising part of holistic approaches for the prevention of dementia.
Keywords: Biological Products; Cognition; Cognitive Dysfunction; Humans; Neuropsychological Tests; Plant Oils; Pomegranate

Epistatic Features and Machine Learning Improve Alzheimer's Disease Risk Prediction Over Polygenic Risk Scores. - Hermes, Stephen; Cady, Janet; Armentrout, Steven; O'Connor, James; Holdaway, Sarah Carlson; Cruchaga, Carlos; Wingo, Thomas; Greytak, Ellen McRae (J Alzheimers Dis, 2024)
BACKGROUND: Polygenic risk scores (PRS) are linear combinations of genetic markers weighted by effect size that are commonly used to predict disease risk. For complex heritable diseases such as late-onset Alzheimer's disease (LOAD), PRS models fail to capture much of the heritability. Additionally, PRS models are highly dependent on the population structure of the data on which effect sizes are assessed and have poor generalizability to new data. OBJECTIVE: The goal of this study is to construct a paragenic risk score that, in addition to single genetic marker data used in PRS, incorporates epistatic interaction features and machine learning methods to predict risk for LOAD. METHODS: We construct a new state-of-the-art genetic model for risk of Alzheimer's disease. Our approach innovates over PRS models in two ways: First, by directly incorporating epistatic interactions between SNP loci using an evolutionary algorithm guided by shared pathway information; and second, by estimating risk via an ensemble of non-linear machine learning models rather than a single linear model. We compare the paragenic model to several PRS models from the literature trained on the same dataset. RESULTS: The paragenic model is significantly more accurate than the PRS models under 10-fold cross-validation, obtaining an AUC of 83% and near-clinically significant matched sensitivity/specificity of 75%. It remains significantly more accurate when evaluated on an independent holdout dataset and maintains accuracy within APOE genotype strata. CONCLUSIONS: Paragenic models show potential for improving disease risk prediction for complex heritable diseases such as LOAD over PRS models.
Keywords: Aged; Alzheimer Disease; Apolipoproteins E; Epistasis, Genetic; Female; Genetic Predisposition to Disease; Genetic Risk Score; Genome-Wide Association Study; Humans; Machine Learning; Male; Models, Genetic; Multifactorial Inheritance; Polymorphism, Single Nucleotide

FACEmemory®, an Innovative Online Platform for Episodic Memory Pre-Screening: Findings from the First 3,000 Participants. - Alegret, Montserrat; García-Gutiérrez, Fernando; Muñoz, Nathalia; Espinosa, Ana; Ortega, Gemma; Lleonart, Núria; Rodríguez, Isabel; Rosende-Roca, Maitee; Pytel, Vanesa; Cantero-Fortiz, Yahveth; Rentz, Dorene M; Marquié, Marta; et al. (J Alzheimers Dis, 2024)
BACKGROUND: The FACEmemory® online platform comprises a complex memory test and sociodemographic, medical, and family questions. This is the first study of a completely self-administered memory test with voice recognition, pre-tested in a memory clinic, sensitive to Alzheimer's disease, using information and communication technologies, and offered freely worldwide. OBJECTIVE: To investigate the demographic and clinical variables associated with the total FACEmemory score, and to identify distinct patterns of memory performance on FACEmemory. METHODS: Data from the first 3,000 subjects who completed the FACEmemory test were analyzed. Descriptive analyses were applied to demographic, FACEmemory, and medical and family variables; t-test and chi-square analyses were used to compare participants with preserved versus impaired performance on FACEmemory (cut-off = 32); multiple linear regression was used to identify variables that modulate FACEmemory performance; and machine learning techniques were applied to identify different memory patterns. RESULTS: Participants had a mean age of 50.57 years and 13.65 years of schooling; 64.07% were women, and 82.10% reported memory complaints with worries. The group with impaired FACEmemory performance (20.40%) was older, had less schooling, and had a higher prevalence of hypertension, diabetes, dyslipidemia, and family history of neurodegenerative disease than the group with preserved performance. Age, schooling, sex, country, and completion of the medical and family history questionnaire were associated with the FACEmemory score. Finally, machine learning techniques identified four patterns of FACEmemory performance: normal, dysexecutive, storage, and completely impaired. CONCLUSIONS: FACEmemory is a promising tool for assessing memory in people with subjective memory complaints and for raising awareness about cognitive decline in the community.

First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys. - Solingapuram Sai, Kiran Kumar; Erichsen, Jennifer M; Gollapelli, Krishna K; Krizan, Ivan; Miller, Mack; Bansode, Avinash; Jorgensen, Mathew J; Register, Thomas; Cazzola, Charles; Gandhi, Reenal; Suman, Julie; Craft, Suzanne (J Alzheimers Dis, 2024)
BACKGROUND: Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. OBJECTIVE: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. METHODS: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. RESULTS: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. CONCLUSIONS: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.
Keywords: Administration, Intranasal; Animals; Brain; Chlorocebus aethiops; Female; Gallium Radioisotopes; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Insulin; Male; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals; Tissue Distribution

The funnel effect of reserves prompted by leisure activities across the Alzheimer's disease continuum. - Serra, Laura; Bonarota, Sabrina; Di Domenico, Carlotta; Caruso, Giulia; Giulietti, Giovanni; Rizzuti, Martina; Assogna, Martina; Rodini, Marta; Mencarelli, Lucia; Di Lorenzo, Francesco; Koch, Giacomo; Fadda, Lucia; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves. OBJECTIVE: This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum. METHODS: 35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses. RESULTS: Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls. CONCLUSIONS: This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Cognition; Cognitive Dysfunction; Cognitive Reserve; Female; Humans; Leisure Activities; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Surveys and Questionnaires

Hippocampal CA1 Pyramidal Neurons Display Sublayer and Circuitry Dependent Degenerative Expression Profiles in Aged Female Down Syndrome Mice. - Alldred, Melissa J; Pidikiti, Harshitha; Ibrahim, Kryillos W; Lee, Sang Han; Heguy, Adriana; Hoffman, Gabriel E; Mufson, Elliott J; Stutzmann, Grace E; Ginsberg, Stephen D (J Alzheimers Dis, 2024)
BACKGROUND: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer's disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region. OBJECTIVE: We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields. METHODS: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region. RESULTS: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry. CONCLUSIONS: CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution.

Hypertension, Cognitive Decline, and Mild Cognitive Impairment Among Diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging Results (SOL-INCA). - Márquez, Freddie; Tarraf, Wassim; Stickel, Ariana M; Gonzalez, Kevin A; Testai, Fernando D; Cai, Jianwen; Gallo, Linda C; Talavera, Gregory A; Daviglus, Martha L; Wassertheil-Smoller, Sylvia; DeCarli, Charles; Schneiderman, Neil; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Hypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos. OBJECTIVE: To assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos. METHODS: This population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008-2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016-2018), with a mean follow-up duration of 7 years (n = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors. RESULTS: Compared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= -0.08; CI = [-0.16;-0.01]; p < 0.05), and processing speed (β= -0.11; CI = [-0.20;-0.02]; p < 0.05). Incident hypertension was not associated with significant change in cognitive performance. Both incident (OR = 1.70; CI = [1.16;2.50]; p < 0.01) and persistent hypertension (OR = 2.13; CI = [1.57;2.88]; p < 0.001) were associated with significantly higher odds ratios of having MCI. CONCLUSIONS: These findings indicate that persistent hypertension is associated with clinical impairment and domain-specific cognitive decline in middle-aged and older Hispanics/Latinos. It underscores the importance of monitoring blood pressure in routine healthcare visits beginning at midlife in this population to reduce the burden of cognitive decline.

An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response. - García-Alberca, José María; de Rojas, Itziar; Sanchez-Mejias, Elisabeth; Garrido-Martín, Diego; Gonzalez-Palma, Laura; Jimenez, Sebastian; Pino-Angeles, Almudena; Cruz-Gamero, Jose Manuel; Mendoza, Silvia; Alarcón-Martín, Emilio; Muñoz-Castro, Clara; Real, Luis Miguel; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. OBJECTIVE: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. METHODS: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. RESULTS: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. CONCLUSIONS: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Humans; Microglia; Phagocytosis; Receptors, Cell Surface

Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study. - Yau, Yu Fung; Cheah, Irwin K; Mahendran, Rathi; Tang, Richard My; Chua, Ru Yuan; Goh, Rachel E S; Feng, Lei; Li, Jialiang; Kua, Ee Heok; Chen, Christopher; Halliwell, Barry (J Alzheimers Dis, 2024)
BACKGROUND: Dementia, particularly Alzheimer's disease, is a major healthcare challenge in ageing societies. OBJECTIVE: This study aimed to investigate the efficacy and safety of a dietary compound, ergothioneine, in delaying cognitive decline in older individuals. METHODS: Nineteen subjects aged 60 or above with mild cognitive impairment were recruited for this double-blinded, randomized, and placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404, registration date: 19/08/2018). Subjects received either ergothioneine (25 mg per capsule) or a placebo, taken 3 times a week for one year. The whole blood profile, markers of renal and liver functions, neurocognitive performance, plasma levels of ergothioneine and its metabolites, and plasma biomarkers related to neurodegeneration were measured across the study. RESULTS: Ergothioneine intake did not alter clinical safety markers (blood counts, kidney and liver function) throughout the study, further validating its safety for human consumption. Subjects receiving ergothioneine demonstrated improved performance in assessment of learning ability and stabilized plasma levels of neurofilament light chain, compared with the placebo group, which saw no improvement in cognitive assessments and a significant increase in neurofilament light chain levels. CONCLUSIONS: Prolonged intake of ergothioneine showed no toxicity in elderly people. Enhanced Rey Auditory Verbal Learning Test performance and stabilized neurofilament light chain levels suggest improvements in memory and learning abilities and a deceleration of neuronal damage, respectively. Our results add to existing data that ergothioneine is safe for extended consumption and may hold the potential to delay cognitive decline in elderly adults.

Long Non-Coding RNA Profile in Genetic Symptomatic and Presymptomatic Frontotemporal Dementia: A GENFI Study. - Serpente, Maria; Fenoglio, Chiara; Arcaro, Marina; Carandini, Tiziana; Sacchi, Luca; Pintus, Manuela; Rotondo, Emanuela; Borracci, Vittoria; Ghezzi, Laura; Bouzigues, Arabella; Russell, Lucy L; Foster, Phoebe H; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood. OBJECTIVE: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). METHODS: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). RESULTS: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. CONCLUSIONS: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.

Mayo Normative Studies: Amyloid and Neurodegeneration Negative Normative Data for the Auditory Verbal Learning Test and Sex-Specific Sensitivity to Mild Cognitive Impairment/Dementia. - Stricker, Nikki H; Christianson, Teresa J; Pudumjee, Shehroo B; Polsinelli, Angelina J; Lundt, Emily S; Frank, Ryan D; Kremers, Walter K; Machulda, Mary M; Fields, Julie A; Jack, Clifford R; Knopman, David S; Graff-Radford, Jonathan; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Conventional normative samples include individuals with undetected Alzheimer's disease neuropathology, lowering test sensitivity for cognitive impairment. OBJECTIVE: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A-N-) for Rey's Auditory Verbal Learning Test (AVLT). We compared these MNS A-N- norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. METHODS: The A-N- sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A-N- norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. RESULTS: Variability associated with age decreased by almost half in the A-N- norm sample relative to the conventional norm sample. Fully-adjusted MNS A-N- norms showed approximately 7- 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1- 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. CONCLUSIONS: A-N- norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A-N- norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.

A Novel Score to Predict Individual Risk for Future Alzheimer's Disease: A Longitudinal Study of the ADNI Cohort. - Guo, Hongxiu; Sun, Shangqi; Yang, Yang; Ma, Rong; Wang, Cailin; Zheng, Siyi; Wang, Xiufeng; Li, Gang (J Alzheimers Dis, 2024)
BACKGROUND: Identifying high-risk individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer's disease (AD) is crucial for early intervention. OBJECTIVE: This study aimed to develop and validate a novel clinical score for personalized estimation of MCI-to-AD conversion. METHODS: The data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Two-thirds of the MCI patients were randomly assigned to a training cohort (n = 478), and the remaining one-third formed the validation cohort (n = 239). Multivariable logistic regression was performed to identify factors associated with MCI-to-AD progression within 4 years. A prediction score was developed based on the regression coefficients derived from the logistic model and tested in the validation cohort. RESULTS: A lipidomics-signature was obtained that showed a significant association with disease progression. The MCI conversion scoring system (ranged from 0 to 14 points), consisting of the lipidomics-signature and five other significant variables (Apolipoprotein ɛ4, Rey Auditory Verbal Learning Test immediate and delayed recall, Alzheimer's Disease Assessment Scale delayed recall test, Functional Activities Questionnaire, and cortical thickness of the AD signature), was constructed. Higher conversion scores were associated with a higher proportion of patients converting to AD. The scoring system demonstrated good discrimination and calibration in both the training cohort (AUC = 0.879, p of Hosmer-Lemeshow test = 0.597) and the validation cohort (AUC = 0.915, p of Hosmer-Lemeshow test = 0.991). The risk classification achieved excellent sensitivity (0.84) and specificity (0.75). CONCLUSIONS: The MCI-to-AD conversion score is a reliable tool for predicting the risk of disease progression in individuals with MCI.

Odor Identification Across Time in Mutation Carriers and Non-Carriers in Autosomal-Dominant Alzheimer's Disease. - Almkvist, Ove; Larsson, Maria; Graff, Caroline (J Alzheimers Dis, 2024)
BACKGROUND: Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain. OBJECTIVE: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease. METHODS: Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification. RESULTS: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC. CONCLUSIONS: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.
Keywords: Alzheimer Disease; Cognition; Cognitive Dysfunction; Humans; Mutation; Odorants; Presenilin-1

Primary cortical cell tri-culture to study effects of amyloid-β on microglia function and neuroinflammatory response. - Kim, Hyehyun; Le, Bryan; Goshi, Noah; Zhu, Kan; Grodzki, Ana Cristina; Lein, Pamela J; Zhao, Min; Seker, Erkin (J Alzheimers Dis, 2024)
BACKGROUND: Microglia play a critical role in neurodegenerative disorders, such as Alzheimer's disease, where alterations in microglial function may result in pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors in vivo, where numerous confounding processes exist, is challenging, and until recently, in vitro models have not allowed sustained culture of critical cell types in the same culture. OBJECTIVE: We employed a rat primary tri-culture (neurons, astrocytes, and microglia) model and compared it to co-culture (neurons and astrocytes) and mono-culture (microglia) to study microglial function (i.e., motility and Aβ clearance) and proteomic response to exogenous Aβ. METHODS: The cultures were exposed to fluorescently-labeled Aβ (FITC-Aβ) particles for varying durations. Epifluorescence microscopy images were analyzed to quantify the number of FITC-Aβ particles and assess cytomorphological features. Cytokine profiles from conditioned media were obtained. Live-cell imaging was employed to extract microglia motility parameters. RESULTS: FITC-Aβ particles were more effectively cleared in the tri-culture compared to the co-culture. This was attributed to microglia engulfing FITC-Aβ particles, as confirmed via epifluorescence and confocal microscopy. FITC-Aβ treatment significantly increased microglia size, but had no significant effect on neuronal surface coverage or astrocyte size. Upon FITC-Aβ treatment, there was a significant increase in proinflammatory cytokines in tri-culture, but not in co-culture. Aβ treatment altered microglia motility evident as a swarming-like motion. CONCLUSIONS: The results suggest that neuron-astrocyte-microglia interactions influence microglia function and highlight the utility of the tri-culture model for studies of neuroinflammation, neurodegeneration, and cell-cell communication.
Keywords: Amyloid beta-Peptides; Animals; Astrocytes; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Cytokines; Microglia; Neuroinflammatory Diseases; Neurons; Rats; Rats, Sprague-Dawley

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease. - Sachdeva, Punya; Narayanan, Kannan Badri; Sinha, Jitendra Kumar; Gupta, Saurabh; Ghosh, Shampa; Singh, Krishna Kumar; Bhaskar, Rakesh; Almutary, Abdulmajeed G; Zothantluanga, James H; Kotta, Kranthi Kumar; Nelson, Vinod Kumar; Paiva-Santos, Ana Cláudia; et al. (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Drug Delivery Systems; Glycogen Synthase Kinase 3 beta; Humans; Insulin; Insulin Resistance

RNA Analysis of Circulating Leukocytes in Patients with Alzheimer's Disease. - Okinaka, Yuka; Shinagawa, Yoshiyuki; Claussen, Carsten; Gul, Sheraz; Matsui, Ikuko; Matsui, Yutaka; Taguchi, Akihiko (J Alzheimers Dis, 2024)
BACKGROUND: One of the key symptoms of Alzheimer's disease (AD) is the impairment of short-term memory. Hippocampal neurogenesis is essential for short-term memory and is known to decrease in patients with AD. Impaired short-term memory and impaired neurogenesis are observed in aged mice alongside changes in RNA expression of gap junction and metabolism-related genes in circulating leukocytes. Moreover, after penetrating the blood-brain barrier via the SDF1/CXCR4 axis, circulating leukocytes directly interact with hippocampal neuronal stem cells via gap junctions. OBJECTIVE: Evaluation of RNA expression profiles in circulating leukocytes in patients with AD. METHODS: Patients with AD (MMSE≧23, n = 10) and age-matched controls (MMSE≧28, n = 10) were enrolled into this study. RNA expression profiles of gap junction and metabolism-related genes in circulating leukocytes were compared between the groups (jRCT: 1050210166). RESULTS: The ratios of gap junction and metabolism-related genes were significantly different between patients with AD and age-matched controls. However, due to large inter-individual variations, there were no statistically significant differences in the level of single RNA expression between these groups. CONCLUSIONS: Our findings suggest a potential connection between the presence of circulating leukocytes and the process of hippocampal neurogenesis in individuals with AD. Analyzing RNA in circulating leukocytes holds promise as a means to offer novel insights into the pathology of AD, distinct from conventional markers.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons. - Gohel, Dhruv; Zhang, Pengyue; Gupta, Amit Kumar; Li, Yichen; Chiang, Chien-Wei; Li, Lang; Hou, Yuan; Pieper, Andrew A; Cummings, Jeffrey; Cheng, Feixiong (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. OBJECTIVE: To investigate the potential therapeutic benefit of sildenafil on AD. METHODS: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. RESULTS: We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. CONCLUSIONS: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.
Keywords: Aged; Alzheimer Disease; Humans; Induced Pluripotent Stem Cells; Medicare; Neurodegenerative Diseases; Neurons; Sildenafil Citrate; Spironolactone; tau Proteins; United States

Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies. - Digma, Leonardino A; Winer, Joseph R; Greicius, Michael D (J Alzheimers Dis, 2024)
With the FDA approval of aducanumab and lecanemab, and with the recent statistically significant phase 3 clinical trial for donanemab, there is growing enthusiasm for anti-amyloid antibodies in the treatment of Alzheimer's disease. Here, we discuss three substantial limitations regarding recent anti-amyloid clinical trials: 1) there is little evidence that amyloid reduction correlates with clinical outcome, 2) the reported efficacy of anti-amyloid therapies may be explained by functional unblinding, and 3) donanemab had no effect on tau burden in its phase 3 trial. Taken together, these observations call into question the efficacy of anti-amyloid therapies.
Keywords: Alzheimer Disease; Amyloidogenic Proteins; Antibodies, Monoclonal, Humanized; Emotions; Humans

Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals. - Sannemann, Lena; Bartels, Claudia; Brosseron, Frederic; Buerger, Katharina; Fliessbach, Klaus; Freiesleben, Silka Dawn; Frommann, Ingo; Glanz, Wenzel; Heneka, Michael T; Janowitz, Daniel; Kilimann, Ingo; Kleineidam, Luca; et al. (J Alzheimers Dis, 2024)
BACKGROUND: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). OBJECTIVE: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. METHODS: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. RESULTS: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6% ) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6% ) and a cluster of participants with overall few symptoms (A+:19.7% ) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ. CONCLUSIONS: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.

A systematic review of lifestyle-based interventions for managing Alzheimer's disease: Insights from randomized controlled trials. - Martínez-López, Sara; Tabone, Mariangela; Clemente-Velasco, Sara; González-Soltero, Maria Del Rocío; Bailén, María; de Lucas, Beatriz; Bressa, Carlo; Domínguez-Balmaseda, Diego; Marín-Muñoz, Juan; Antúnez, Carmen; Gálvez, Beatriz G; Larrosa, Mar (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) presents a significant challenge in healthcare, prompting exploration into non-pharmacological interventions to complement traditional treatments. OBJECTIVE: This systematic review explores the efficacy of lifestyle-based interventions in managing AD. METHODS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus between 2018 and 2023, selecting randomized controlled trials examining factors such as exercise, diet, stress, and cognitive training in AD patients. RESULTS: The review revealed physical exercise as the predominant non-pharmacological intervention, accompanied by dietary modifications, cognitive training, and therapies such as mindfulness and music. While exercise demonstrated improvements in quality of life, its cognitive benefits were limited. Modified diets, such as Atkins and ketogenic, displayed inconsistent effects on cognitive function but influenced other health-related parameters. Additionally, probiotic therapy and novel cognitive training technologies were explored. CONCLUSIONS: Despite some interventions showing promise in enhancing cognitive function and slowing disease progression, uncertainties remain regarding the dose-response relationship, underlying mechanisms, and potential synergistic effects. Moreover, consideration of genetic and sex-based disparities is warranted. This synthesis underscores the need for further research to elucidate the nuances of non-pharmacological interventions in managing AD effectively. PROSPERO REGISTRATION NUMBER: CRD42023432823.
Keywords: Alzheimer Disease; Exercise; Humans; Life Style; Quality of Life; Randomized Controlled Trials as Topic

Transcriptomic Profiling Reveals Neuroinflammation in the Corpus Callosum of a Transgenic Mouse Model of Alzheimer's Disease. - Takase, Hajime; Hamanaka, Gen; Hoshino, Tomonori; Ohtomo, Ryo; Guo, Shuzhen; Mandeville, Emiri T; Lo, Eng H; Arai, Ken (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. OBJECTIVE: This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. METHODS: We conducted behavioral tests for spatial learning and memory in 5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. RESULTS: Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1, Per2, and Cry1 is also observed. CONCLUSIONS: This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies.
Keywords: Alzheimer Disease; Animals; Corpus Callosum; Disease Models, Animal; Gene Expression Profiling; Mice; Mice, Transgenic; Neuroinflammatory Diseases

Unveiling New Strategies Facilitating the Implementation of Artificial Intelligence in Neuroimaging for the Early Detection of Alzheimer's Disease. - Etekochay, Maudlyn O; Amaravadhi, Amoolya Rao; González, Gabriel Villarrubia; Atanasov, Atanas G; Matin, Maima; Mofatteh, Mohammad; Steinbusch, Harry Wilhelm; Tesfaye, Tadele; Praticò, Domenico (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a global impact. The past few decades have witnessed significant strides in comprehending the underlying pathophysiological mechanisms and developing diagnostic methodologies for AD, such as neuroimaging approaches. Neuroimaging techniques, including positron emission tomography and magnetic resonance imaging, have revolutionized the field by providing valuable insights into the structural and functional alterations in the brains of individuals with AD. These imaging modalities enable the detection of early biomarkers such as amyloid-β plaques and tau protein tangles, facilitating early and precise diagnosis. Furthermore, the emerging technologies encompassing blood-based biomarkers and neurochemical profiling exhibit promising results in the identification of specific molecular signatures for AD. The integration of machine learning algorithms and artificial intelligence has enhanced the predictive capacity of these diagnostic tools when analyzing complex datasets. In this review article, we will highlight not only some of the most used diagnostic imaging approaches in neurodegeneration research but focus much more on new tools like artificial intelligence, emphasizing their application in the realm of AD. These advancements hold immense potential for early detection and intervention, thereby paving the way for personalized therapeutic strategies and ultimately augmenting the quality of life for individuals affected by AD.
Keywords: Alzheimer Disease; Artificial Intelligence; Biomarkers; Brain; Early Diagnosis; Humans; Neuroimaging; Positron-Emission Tomography

Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors. - Greenblatt, Charles L; Lathe, Richard (J Alzheimers Dis, 2024)
Vaccines such as Bacille Calmette-Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.
Keywords: Adjuvants, Immunologic; BCG Vaccine; Dementia; Humans; Ligands; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia. - Greenblatt, Charles L; Lathe, Richard (J Alzheimers Dis, 2024)
There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.
Keywords: Adjuvants, Immunologic; Aged; Alzheimer Disease; BCG Vaccine; Humans; Tuberculosis Vaccines

Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease. - Lilek, Jaclyn; Ajroud, Kaouther; Feldman, Alexander Z; Krishnamachari, Sesha; Ghourchian, Shadi; Gefen, Tamar; Spencer, Callen L; Kawles, Allegra; Mao, Qinwen; Tranovich, Jessica F; Jack, Clifford R; Mesulam, M-Marsel; et al. (J Alzheimers Dis, 2023)

Alzheimer's Disease: A Systems View Provides a Unifying Explanation of Its Development. - Grobler, Corlia; van Tongeren, Marvi; Gettemans, Jan; Kell, Douglas B; Pretorius, Etheresia (J Alzheimers Dis, 2023)
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people globally. It is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles, consisting of amyloid-β and hyperphosphorylated tau proteins, respectively. Despite global research efforts, there is currently no cure available, due in part to an incomplete understanding of the disease pathogenesis. Numerous possible mechanisms, or hypotheses, explaining the origins of sporadic or late-onset AD have been proposed, including the amyloid-β, inflammatory, vascular, and infectious hypotheses. However, despite ample evidence, the failure of multiple trial drugs at the clinical stage illuminates the possible pitfalls of these hypotheses. Systems biology is a strategy which aims to elucidate the interactions between parts of a whole. Using this approach, the current paper shows how the four previously mentioned hypotheses of AD pathogenesis can be intricately connected. This approach allows for seemingly contradictory evidence to be unified in a system-focused explanation of sporadic AD development. Within this view, it is seen that infectious agents, such as P. gingivalis, may play a central role. The data presented here shows that when present, P. gingivalis or its virulence factors, such as gingipains, may induce or exacerbate pathologies underlying sporadic AD. This evidence supports the view that infectious agents, and specifically P. gingivalis, may be suitable treatment targets in AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Humans; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins

Apathy as a Predictor of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Texas Alzheimer's Research and Care Consortium (TARCC) Cohort-Based Analysis. - Salem, Haitham; Suchting, Robert; Gonzales, Mitzi M; Seshadri, Sudha; Teixeira, Antônio L (J Alzheimers Dis, 2023)
BACKGROUND: Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). OBJECTIVE: To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC) cohort. METHODS: Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory -Questionnaire (NPI-Q) completed by family members or caregivers. The final dataset included 2,897 observations from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest. RESULTS: Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n = 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n = 158) versus without apathy (n = 934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion. CONCLUSIONS: Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery.

Aspirin Use and Risk of Alzheimer's Disease: A 2-Sample Mendelian Randomization Study. - Ding, Pingjian; Gorenflo, Maria P; Zhu, Xiaofeng; Xu, Rong (J Alzheimers Dis, 2023)
BACKGROUND: Observational studies have shown inconsistent findings of the relationships between aspirin use and the risk of Alzheimer's disease (AD). OBJECTIVE: Since residual confounding and reverse causality were challenging issues inherent in observational studies, we conducted a 2-sample Mendelian randomization analysis (MR) to investigate whether aspirin use was causally associated with the risk of AD. METHODS: We conducted 2-sample MR analyses utilizing summary genetic association statistics to estimate the potential causal relationship between aspirin use and AD. Single-nucleotide variants associated with aspirin use in a genome-wide association study (GWAS) of UK Biobank were considered as genetic proxies for aspirin use. The GWAS summary-level data of AD were derived from a meta-analysis of GWAS data from the International Genomics of Alzheimer's Project (IGAP) stage I. RESULTS: Univariable MR analysis based on these two large GWAS data sources showed that genetically proxied aspirin use was associated with a decreased risk of AD (Odds Ratio (OR): 0.87; 95%CI: 0.77-0.99). In multivariate MR analyses, the causal estimates remained significant after adjusting for chronic pain, inflammation, heart failure (OR = 0.88, 95%CI = 0.78-0.98), or stroke (OR = 0.87, 95%CI = 0.77-0.99), but was attenuated when adjusting for coronary heart disease, blood pressure, and blood lipids. CONCLUSION: Findings from this MR analysis suggest a genetic protective effect of aspirin use on AD, possibly influenced by coronary heart disease, blood pressure, and lipid levels.

Association of Alcohol Consumption with Cognition in Older Population: The A4 Study. - Nallapu, Bhargav T; Petersen, Kellen K; Lipton, Richard B; Grober, Ellen; Sperling, Reisa A; Ezzati, Ali (J Alzheimers Dis, 2023)
BACKGROUND: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia. OBJECTIVE: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain. METHODS: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels. RESULTS: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ- subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant. CONCLUSION: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.

Association of Interleukin-6 and Interleukin-8 with Cognitive Decline in an Asian Memory Clinic Population. - Teoh, Nicole Shu Ning; Gyanwali, Bibek; Lai, Mitchell K P; Chai, Yuek Ling; Chong, Joyce R; Chong, Eddie Jun Yi; Chen, Christopher; Tan, Chuen Seng; Hilal, Saima (J Alzheimers Dis, 2023)
BACKGROUND: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. OBJECTIVE: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. METHODS: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. RESULTS: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. CONCLUSION: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.
Keywords: Aged; Biomarkers; Canada; Cognition; Cognitive Dysfunction; Female; Humans; Interleukin-6; Interleukin-8; Male; Neuroinflammatory Diseases; Neuropsychological Tests

Associations Between Ambient Air Pollution and Cognitive Abilities from Midlife to Early Old Age: Modification by APOE Genotype. - Franz, Carol E; Gustavson, Daniel E; Elman, Jeremy A; Fennema-Notestine, Christine; Hagler, Donald J; Baraff, Aaron; Tu, Xin M; Wu, Tsung-Chin; De Anda, Jaden; Beck, Asad; Kaufman, Joel D; Whitsel, Nathan; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD). OBJECTIVE: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife. METHODS: Participants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates. RESULTS: Performance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed. CONCLUSION: These results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

Associations Between Local Area Deprivation and Physical Activity Participation in People with Cognitive Impairment in the North East of England. - Mc Ardle, Ríona; Hamilton, Calum; Del Din, Silvia; Kingston, Andrew; Robinson, Louise; Galna, Brook; Thomas, Alan J; Rochester, Lynn (J Alzheimers Dis, 2023)
BACKGROUND: Promoting physical activity, such as habitual walking behaviors, in people with cognitive impairment may support their ability to remain independent with a good quality of life for longer. However, people with cognitive impairment participate in less physical activity compared to cognitively unimpaired older adults. The local area in which people live may significantly impact abilities to participate in physical activity. For example, people who live in more deprived areas may have less safe and walkable routes. OBJECTIVE: To examine this further, this study aimed to explore associations between local area deprivation and physical activity in people with cognitive impairment and cognitively unimpaired older adults (controls). METHODS: 87 participants with cognitive impairment (mild cognitive impairment or dementia) and 27 older adult controls from the North East of England were included in this analysis. Participants wore a tri-axial wearable accelerometer (AX3, Axivity) on their lower backs continuously for seven days. The primary physical activity outcome was daily step count. Individuals' neighborhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between local area deprivation and daily step count in people with cognitive impairment and controls. RESULTS: Key findings indicated that there was no association between local area deprivation and daily step count in people with cognitive impairment, but higher deprivation was associated with lower daily steps for controls. CONCLUSION: These findings suggest that cognitive impairment may be associated with lower participation in physical activity which supersedes the influence of local area deprivation observed in normal aging.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings. - Gonzalez, Christopher; Mimmack, Kayden J; Amariglio, Rebecca E; Becker, J Alex; Chhatwal, Jasmeer P; Fitzpatrick, Colleen D; Gatchel, Jennifer R; Johnson, Keith A; Katz, Zoe S; Kuppe, Madeline K; Locascio, Joseph J; Udeogu, Onyinye J; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Cognitive Dysfunction; Entorhinal Cortex; Humans; Positron-Emission Tomography; tau Proteins

Cardiorespiratory Fitness Attenuates the Deleterious Effects of Sleep Apnea on Cerebral Structure and Perfusion in the Wisconsin Sleep Cohort Study. - Edmunds, Kyle J; Driscoll, Ira; Hagen, Erika W; Barnet, Jodi H; Ravelo, Laurel A; Plante, David T; Gaitán, Julian M; Lose, Sarah R; Motovylyak, Alice; Bendlin, Barbara B; Okonkwo, Ozioma C; Peppard, Paul E (J Alzheimers Dis, 2023)
BACKGROUND: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep. OBJECTIVE: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion. METHODS: Using data from a cross-sectional sample of participants (n = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants' sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]). RESULTS: OSA severity was associated with reduced total GM volume (β=-0.064; SE = 0.023; p = 0.007), greater total WM lesion volume (interaction p = 0.023), and greater WMHs (interaction p = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps <  0.05). CONCLUSION: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults.

Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimer's Disease. - van den Berg, Emma; Nilsson, Johanna; Kersten, Iris; Brinkmalm, Gunnar; de Kort, Anna M; Klijn, Catharina J M; Schreuder, Floris H B M; Jäkel, Lieke; Gobom, Johan; Portelius, Erik; Zetterberg, Henrik; Brinkmalm, Ann; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. OBJECTIVE: We therefore aimed to investigate synaptic dysfunction in CAA. METHODS: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. RESULTS: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). CONCLUSION: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Characterizing Performance Gaps of a Code-Based Dementia Algorithm in a Population-Based Cohort of Cognitive Aging. - Vassilaki, Maria; Fu, Sunyang; Christenson, Luke R; Garg, Muskan; Petersen, Ronald C; St Sauver, Jennifer; Sohn, Sunghwan (J Alzheimers Dis, 2023)
BACKGROUND: Multiple algorithms with variable performance have been developed to identify dementia using combinations of billing codes and medication data that are widely available from electronic health records (EHR). If the characteristics of misclassified patients are clearly identified, modifying existing algorithms to improve performance may be possible. OBJECTIVE: To examine the performance of a code-based algorithm to identify dementia cases in the population-based Mayo Clinic Study of Aging (MCSA) where dementia diagnosis (i.e., reference standard) is actively assessed through routine follow-up and describe the characteristics of persons incorrectly categorized. METHODS: There were 5,316 participants (age at baseline (mean (SD)): 73.3 (9.68) years; 50.7% male) without dementia at baseline and available EHR data. ICD-9/10 codes and prescription medications for dementia were extracted between baseline and one year after an MCSA dementia diagnosis or last follow-up. Fisher's exact or Kruskal-Wallis tests were used to compare characteristics between groups. RESULTS: Algorithm sensitivity and specificity were 0.70 (95% CI: 0.67, 0.74) and 0.95 (95% CI: 0.95, 0.96). False positives (i.e., participants falsely diagnosed with dementia by the algorithm) were older, with higher Charlson comorbidity index, more likely to have mild cognitive impairment (MCI), and longer follow-up (versus true negatives). False negatives (versus true positives) were older, more likely to have MCI, or have more functional limitations. CONCLUSIONS: We observed a moderate-high performance of the code-based diagnosis method against the population-based MCSA reference standard dementia diagnosis. Older participants and those with MCI at baseline were more likely to be misclassified.
Keywords: Alzheimer Disease; Cognitive Aging; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Male

Cleveland Clinic Cognitive Battery (C3B): Normative, Reliability, and Validation Studies of a Self-Administered Computerized Tool for Screening Cognitive Dysfunction in Primary Care. - Rao, Stephen M; Galioto, Rachel; Sokolowski, Megan; Pierce, Madelyn; Penn, Lisa; Sturtevant, Anna; Skugor, Blazenka; Anstead, Brent; Leverenz, James B; Schindler, David; Blum, David; Alberts, Jay L; et al. (J Alzheimers Dis, 2023)
BACKGROUND: The self-administered iPad-based Cleveland Clinic Cognitive Battery (C3B) was designed specifically for the efficient screening of cognitive functioning of older adults in a primary care setting. OBJECTIVE: 1) Generate regression-based norms from healthy participants to enable demographic corrections to facilitate clinical interpretation; 2) estimate test-retest reliability and practice effects; 3) examine ability to discriminate mild cognitive impairment (MCI) from healthy aging; 4) d etermine validity of screening in a distracting clinical environment; and 5) determine completion rates and patient satisfaction in a primary care setting. METHODS: Study 1 (S1) recruited a stratified sample of 428 healthy adults, ages 18-89, to generate regression-based equations. S2 assessed 2-week test-retest reliability and practice effects in 30 healthy elders. S3 recruited 30 MCI patients and 30 demographically-matched healthy controls. In S4, 30 healthy elders self-administered the C3B in a distracting environment and in a quiet private room in counterbalanced order. In a demonstration project, 470 consecutive primary care patients were administered the C3B as part of routine clinical care (S5). RESULTS: C3B performance was primarily influenced by age, education, and race (S1), had acceptably high test-retest reliability and minimal practice effects (S2), discriminated MCI from healthy controls (S3), was not negatively impacted by a distracting clinical environment (S4), had high completion rates (>92%) and positive ratings from primary care patients (S5). CONCLUSION: The C3B is a computerized cognitive screening tool that is reliable, validated, self-administered, and is conducive to integration into a busy primary care clinical workflow for detecting MCI, early Alzheimer's disease, and other related dementias.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Cognition; Cognitive Dysfunction; Humans; Middle Aged; Neuropsychological Tests; Primary Health Care; Reproducibility of Results; Young Adult

Cognitive and Neuropsychological Profiles in Alzheimer's Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies. - Walker, Jamie M; Gonzales, Mitzi M; Goette, William; Farrell, Kurt; White Iii, Charles L; Crary, John F; Richardson, Timothy E (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. OBJECTIVE: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). METHODS: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I-IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset. RESULTS: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. CONCLUSION: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Cognition; Executive Function; Humans; Tauopathies

Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease. - Zhu, Carolyn W; Gu, Yian; Kociolek, Anton J; Fernandez, Kayri K; Cosentino, Stephanie; Stern, Yaakov (J Alzheimers Dis, 2023)
BACKGROUND: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. OBJECTIVE: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer's disease (AD) or DLB and had autopsy confirmed diagnosis. METHODS: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n = 44, DLB: n = 14) and also had autopsy-confirmed diagnoses of pure AD (n = 32), mixed AD+Lewy body (LB) (n = 5), or pure LB (n = 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. RESULTS: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. CONCLUSION: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-DLB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

Costs of Dementia in Low- And Middle-Income Countries: A Systematic Review. - Kenne Malaha, Angeladine; Thébaut, Clémence; Achille, Dayna; Preux, Pierre-Marie; Guerchet, Maëlenn (J Alzheimers Dis, 2023)
BACKGROUND: The proportion of people living with dementia in low- and middle-income countries (LMICs) is expected to reach 71% by 2050. Appraising the economic burden of the disease may contribute to strategic policy planning. OBJECTIVE: To review studies conducted on the costs of dementia in LMICs, describe their methodology and summarize available costs estimates. METHODS: Systematic review, including a search of health, economics, and social science bibliographic databases. No date or language restrictions were applied. All studies with a direct measure of the costs of dementia care were included. RESULTS: Of the 6,843 publications reviewed, 17 studies from 11 LMICs were included. Costs of dementia tended to increase with the severity of the disease. Medical costs were greater in the mild stage, while social and informal care costs were highest in the moderate and severe stages. Annual cost estimates per patient ranged from PPP$131.0 to PPP$31,188.8 for medical costs; from PPP$16.1 to PPP$10,581.7 for social care services and from PPP$140.0 to PPP$25,798 for informal care. Overall, dementia care can cost from PPP$479.0 to PPP$66,143.6 per year for a single patient. CONCLUSION: Few studies have been conducted on the costs of dementia in LMICs, and none so far in Africa. There seems to be a need to provide accurate data on the burden of disease in these countries to guide public health policies in the coming decades.
Keywords: Cost of Illness; Dementia; Developing Countries; Health Care Costs; Health Expenditures; Humans

COVID-19 as a Risk Factor for Alzheimer's Disease. - Golzari-Sorkheh, Mahdieh; Weaver, Donald F; Reed, Mark A (J Alzheimers Dis, 2023)
Severe acute respiratory disease coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although a primarily respiratory disease, recent reports indicate that it also affects the central nervous system (CNS). Over 25% of COVID-19 patients report neurological symptoms such as memory loss, anosmia, hyposmia, confusion, and headaches. The neurological outcomes may be a result of viral entry into the CNS and/or resulting neuroinflammation, both of which underlie an elevated risk for Alzheimer's disease (AD). Herein, we ask: Is COVID-19 a risk factor for AD? To answer, we identify the literature and review mechanisms by which COVID-19-mediated neuroinflammation can contribute to the development of AD, evaluate the effects of acute versus chronic phases of infection, and lastly, discuss potential therapeutics to address the rising rates of COVID-19 neurological sequelae.
Keywords: Alzheimer Disease; COVID-19; Humans; Nervous System Diseases; Neuroinflammatory Diseases; Risk Factors; SARS-CoV-2

Is Dementia Associated with COVID-19 Mortality? A Multicenter Retrospective Cohort Study Conducted in 50 Hospitals in Germany. - Kostev, Karel; Gessler, Nele; Wohlmuth, Peter; Arnold, Dirk; Bein, Berthold; Bohlken, Jens; Herrlinger, Klaus; Jacob, Louis; Koyanagi, Ai; Nowak, Lorenz; Smith, Lee; Wesseler, Claas; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Dementia has been identified as a major predictor of mortality associated with COVID-19. OBJECTIVE: The objective of this study was to investigate the association between dementia and mortality in COVID-19 inpatients in Germany across a longer interval during the pandemic. METHODS: This retrospective study was based on anonymized data from 50 hospitals in Germany and included patients with a confirmed COVID-19 diagnosis hospitalized between March 11, 2020 and July, 20, 2022. The main outcome of the study was the association of mortality during inpatient stays with dementia diagnosis, which was studied using multivariable logistic regression adjusted for age, sex, and comorbidities as well as univariate logistic regression for matched pairs. RESULTS: Of 28,311 patients diagnosed with COVID-19, 11.3% had a diagnosis of dementia. Prior to matching, 26.5% of dementia patients and 11.5% of non-dementia patients died; the difference decreased to 26.5% of dementia versus 21.7% of non-dementia patients within the matched pairs (n = 3,317). This corresponded to an increase in the risk of death associated with dementia (OR = 1.33; 95% CI: 1.16-1.46) in the univariate regression conducted for matched pairs. CONCLUSION: Although dementia was associated with COVID-19 mortality, the association was weaker than in previously published studies. Further studies are needed to better understand whether and how pre-existing neuropsychiatric conditions such as dementia may impact the course and outcome of COVID-19.
Keywords: COVID-19; COVID-19 Testing; Dementia; Germany; Hospitalization; Hospitals; Humans; Mortality; Retrospective Studies

Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease. - Guieysse, Thomas; Lamothe, Roxane; Houot, Marion; Razafimahatratra, Solofo; Medani, Takfarinas; Lejeune, François-Xavier; Dreyfus, Gérard; Klarsfeld, André; Pantazis, Dimitrios; Koechlin, Etienne; Andrade, Katia (J Alzheimers Dis, 2023)
BACKGROUND: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD). OBJECTIVES: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. METHODS: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment. RESULTS: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. CONCLUSIONS: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.
Keywords: Agnosia; Alzheimer Disease; Brain; Caregivers; Humans; Neuropsychological Tests; Prodromal Symptoms

Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding. - Grant, William B; Blake, Steven M (J Alzheimers Dis, 2023)
Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.
Keywords: Alzheimer Disease; Cross-Sectional Studies; Diet; Humans; Prospective Studies; Risk Factors

Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France. - Bogdan, Anamaria; Fabre, Roxane; Desmidt, Thomas; Golebiowski, Jérôme; Topin, Jérémie; Bethus, Ingrid; Hanon, Olivier; Boutoleau-Bretonnière, Claire; Wagemann, Nathalie; Annweiler, Cedric; Ousset, Pierre-Jean; Godefroy, Olivier; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. OBJECTIVE: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. METHODS: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. RESULTS: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. CONCLUSION: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely-compared to depression-to be associated with conversion to dementia.

Early Amnestic Mild Cognitive Impairment Is Associated with Reduced Total Cerebral Blood Flow with no Brain Tissue Loss. - Liu, Che; Lee, Sang H; Loewenstein, David A; Galvin, James E; Levin, Bonnie E; McKinney, Alexander; Alperin, Noam (J Alzheimers Dis, 2023)
BACKGROUND: Lower cerebral blood flow (CBF) and brain atrophy are linked to Alzheimer's disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. OBJECTIVE: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. METHODS: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. RESULTS: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while volume differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485). CONCLUSION: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss.

The Effect of Exercise on Falls in People Living with Dementia: A Systematic Review. - Jehu, Deborah A; Davis, Jennifer C; Gill, Jessica; Oke, Olabamibo; Liu-Ambrose, Teresa (J Alzheimers Dis, 2023)
BACKGROUND: People living with dementia (PWD) are at a heightened risk for falls. However, the effects of exercise on falls in PWD are unclear. OBJECTIVE: To conduct a systematic review of randomized controlled trials (RCTs) examining the efficacy of exercise to reduce falls, recurrent falls, and injurious falls relative to usual care among PWD. METHODS: We included peer-reviewed RCTs evaluating any exercise mode on falls and related injuries among medically diagnosed PWD aged ≥55years (international prospective register of systematic reviews (PROSPERO) ID:CRD42021254637). We excluded studies that did not solely involve PWD and were not the primary publication examining falls. We searched the Cochrane Dementia and Cognitive Improvement Group's Specialized Register and grey literature on 08/19/2020 and 04/11/2022; topical categories included dementia, exercise, RCTs, and falls. We evaluated the risk of bias (ROB) using the Cochrane ROB Tool-2 and study quality using the Consolidated Standards of Reporting Trials. RESULTS: Twelve studies were included (n = 1,827; age = 81.3±7.0 years; female = 59.3%; Mini-Mental State Examination = 20.1±4.3 points; intervention duration = 27.8±18.5 weeks; adherence = 75.5±16.2%; attrition = 21.0±12.4%). Exercise reduced falls in two studies [Incidence Rate Ratio (IRR) range = 0.16 to 0.66; fall rate range: intervention = 1.35-3.76 falls/year, control = 3.07-12.21 falls/year]; all other studies (n = 10) reported null findings. Exercise did not reduce recurrent falls (n = 0/2) or injurious falls (n = 0/5). The RoB assessment ranged from some concerns (n = 9) to high RoB (n = 3); no studies were powered for falls. The quality of reporting was good (78.8±11.4%). CONCLUSION: There was insufficient evidence to suggest that exercise reduces falls, recurrent falls, or injurious falls among PWD. Well-designed studies powered for falls are needed.
Keywords: Dementia; Exercise; Female; Humans; Independent Living

Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups. - Bouges, Shenikqua; Fischer, Barbara; Norton, Derek L; Wyman, Mary F; Lambrou, Nickolas; Zuelsdorff, Megan; Van Hulle, Carol A; Ennis, Gilda E; James, Taryn T; Johnson, Adrienne L; Chin, Nathaniel; Carlsson, Cynthia M; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer's disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. OBJECTIVE: Examine association of MetS features and processing speed and executive function across three racial groups. METHODS: Cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. RESULTS: Participant sample sizes varied by outcome analyzed (N = 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A. CONCLUSION: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Effects of Striatal Amyloidosis on the Dopaminergic System and Behavior: A Comparative Study in Male and Female 5XFAD Mice. - Lansdell, Theresa A; Xu, Hui; Galligan, James J; Dorrance, Anne M (J Alzheimers Dis, 2023)
BACKGROUND: Nearly two-thirds of patients diagnosed with Alzheimer's disease (AD) are female. In addition, female patients with AD have more significant cognitive impairment than males at the same disease stage. This disparity suggests there are sex differences in AD progression. While females appear to be more affected by AD, most published behavioral studies utilize male mice. In humans, there is an association between antecedent attention-deficit/hyperactivity disorder and increased risk of dementia. Functional connectivity studies indicate that dysfunctional cortico-striatal networks contribute to hyperactivity in attention deficit hyperactivity disorder. Higher plaque density in the striatum accurately predicts the presence of clinical AD pathology. In addition, there is a link between AD-related memory dysfunction and dysfunctional dopamine signaling. OBJECTIVE: With the need to consider sex as a biological variable, we investigated the influence of sex on striatal plaque burden, dopaminergic signaling, and behavior in prodromal 5XFAD mice. METHODS: Six-month-old male and female 5XFAD and C57BL/6J mice were evaluated for striatal amyloid plaque burden, locomotive behavior, and changes in dopaminergic machinery in the striatum. RESULTS: 5XFAD female mice had a higher striatal amyloid plaque burden than male 5XFAD mice. 5XFAD females, but not males, were hyperactive. Hyperactivity in female 5XFAD mice was associated with increased striatal plaque burden and changes in dopamine signaling in the dorsal striatum. CONCLUSION: Our results indicate that the progression of amyloidosis involves the striatum in females to a greater extent than in males. These studies have significant implications for using male-only cohorts in the study of AD progression.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Disease Models, Animal; Dopamine; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid

Efficacy of Souvenaid® Combined with Acetylcholinesterase Inhibitors in the Treatment of Mild Alzheimer's Disease. - García-Alberca, José María; Gris, Esther; de la Guía, Paz; Mendoza, Silvia; de la Rica, María López (J Alzheimers Dis, 2023)
BACKGROUND: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer's disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known. OBJECTIVE: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world. METHODS: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n = 66), AChEI alone (n = 84), and Souvenaid+AChEI (n = 70). Treatment effects were evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores. RESULTS: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p < 0.001), RAVLT (p < 0.0001), SVFT (p = 0.002), PVFT (p = 0.007), TMTA (p = 0.039), TMTB (p = 0.001), and NPI (p < 0.0001) compared to AChEI alone. CONCLUSION: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD.

Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease. - Guo, Xiaodi; Zhang, Guoxin; Peng, Qinyu; Huang, Liqin; Zhang, Zhaohui; Zhang, Zhentao (J Alzheimers Dis, 2023)
Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.
Keywords: Alzheimer Disease; Apolipoprotein E4; Glymphatic System; Humans; Lymphatic System; Lymphatic Vessels

Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals. - Raji, Cyrus A; Meysami, Somayeh; Hashemi, Sam; Garg, Saurabh; Akbari, Nasrin; Ahmed, Gouda; Chodakiewitz, Yosef Gavriel; Nguyen, Thanh Duc; Niotis, Kellyann; Merrill, David A; Attariwala, Rajpaul (J Alzheimers Dis, 2023)
BACKGROUND: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk. OBJECTIVE: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. METHODS: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. RESULTS: Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5). CONCLUSIONS: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

Exploring Reasons for Differential Vulnerability and Alzheimer's Disease Risk in Racial and Ethnic Minorities. - Daniel, E Valerie; Kleiman, Michael J; Galvin, James E (J Alzheimers Dis, 2023)
BACKGROUND: African American and Hispanic older adults are reported to have up to a 2-fold higher risk of Alzheimer's disease and related disorders (ADRD), but the reasons for this increased vulnerability have not been fully explored. The Vulnerability Index (VI) was designed to identify individuals who are at risk of developing cognitive impairment in the future, capturing 12 sociodemographic variables and modifiable medical comorbidities associated with higher ADRD risk. However, a prior limitation of the VI was that the original study cohort had limited diversity. We examined the association of the VI within and between non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment and different socioeconomic strata enrolled in a community-based dementia screening study. OBJECTIVE: To explore reasons for reported higher ADRD vulnerability in African Americans and Hispanics. METHODS: In a cross-sectional study of 300 non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment, we studied the association between cognitive status, the VI, and socioeconomic status (SES). RESULTS: When considering race/ethnicity, the presence of more vascular comorbidities drove greater vulnerability. When considering SES, vascular comorbidities played a less prominent role suggesting resources and access to care drives risk. The VI had differential effects on cognitive performance with the greatest effect in the earlier stages of impairment. CONCLUSION: Findings from this study provide a deeper understanding of the differential risk of ADRD in multicultural older adults captured by the VI and how barriers to healthcare access may increase vulnerability in racial/ethnic minorities.
Keywords: Aged; Alzheimer Disease; Cross-Sectional Studies; Ethnic and Racial Minorities; Ethnicity; Humans; White People

Exposure to World Trade Center Dust Exacerbates Cognitive Impairment and Evokes a Central and Peripheral Pro-Inflammatory Transcriptional Profile in an Animal Model of Alzheimer's Disease. - Iban-Arias, Ruth; Trageser, Kyle J; Yang, Eun-Jeong; Griggs, Elizabeth; Radu, Aurelian; Naughton, Sean; Al Rahim, Md; Tatsunori, Oguchi; Raval, Urdhva; Palmieri, Joshua; Huang, Zerlina; Chen, Lung-Chi; et al. (J Alzheimers Dis, 2023)
BACKGROUND: The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life. OBJECTIVE: We hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype. METHODS: 5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR. RESULTS: Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption. CONCLUSION: These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.
Keywords: Alzheimer Disease; Animals; Cognitive Dysfunction; Dust; Mice; Models, Animal; September 11 Terrorist Attacks

Helicobacter pylori Infection Is Associated with Long-Term Cognitive Decline in Older Adults: A Two-Year Follow-Up Study. - Wang, Jian; Yu, Neng-Wei; Wang, Duo-Zi; Guo, Lei; Yang, Shu; Zheng, Bo; Guo, Fu-Qiang; Wang, Jian-Hong (J Alzheimers Dis, 2023)
BACKGROUND: Previous cross-sectional studies have identified a possible link between Helicobacter pylori (H. pylori) infection and dementia. However, the association of H. pylori infection with longitudinal cognitive decline has rarely been investigated. OBJECTIVE: This cohort study aims to demonstrate the effects of H. pylori infection on longitudinal cognitive decline. METHODS: This cohort study recruited 268 subjects with memory complaints. Among these subjects, 72 had a history of H. pylori infection, and the rest 196 subjects had no H. pylori infection. These subjects were followed up for 24 months and received cognitive assessment in fixed intervals of 12 months. RESULTS: At baseline, H. pylori infected, and uninfected participants had no difference in MMSE scores. At 2 years of follow-up, H. pylori infected participants had lower MMSE scores than uninfected participants. H. pylori infection was associated with an increased risk of longitudinal cognitive decline, as defined by a decrease of MMSE of 3 points or more during follow-up, adjusting for age, sex, education, APOEɛ4 genotype, hypertension, diabetes, hyperlipidemia, and smoking history (HR: 2.701; 95% CI: 1.392 to 5.242). H. pylori infection was associated with larger cognitive decline during follow-up, adjusting for the above covariates (standardized coefficient: 0.282, p < 0.001). Furthermore, H. pylori infected subjects had significantly higher speed of cognitive decline than uninfected subjects during follow-up, adjusting for the above covariates. CONCLUSION: H. pylori infection increases the risk of longitudinal cognitive decline in older subjects with memory complaints. This study is helpful for further understanding the association between infection and dementia.

High-Quality Sleep Mitigates ABCA7-Related Generalization Deficits in Healthy Older African Americans. - Sinha, Neha; Fausto, Bernadette A; Mander, Bryce; Gluck, Mark A (J Alzheimers Dis, 2023)
BACKGROUND: Both sleep deficiencies and Alzheimer's disease (AD) disproportionately affect older African Americans. Genetic susceptibility to AD further compounds risk for cognitive decline in this population. Aside from APOE ɛ4, ABCA7 rs115550680 is the strongest genetic locus associated with late-onset AD in African Americans. While sleep and ABCA7 rs115550680 independently influence late-life cognitive outcomes, we know too little about the interplay between these two factors on cognitive function. OBJECTIVE: We investigated the interaction between sleep and ABCA7 rs115550680 on hippocampal-dependent cognitive function in older African Americans. METHODS: One-hundred fourteen cognitively healthy older African Americans were genotyped for ABCA7 risk (n = 57 carriers of risk "G" allele; n = 57 non-carriers), responded to lifestyle questionnaires, and completed a cognitive battery. Sleep was assessed via a self-reported rating of sleep quality (poor, average, good). Covariates included age and years of education. RESULTS: Using ANCOVA, we found that carriers of the risk genotype who reported poor or average sleep quality demonstrated significantly poorer generalization of prior learning¾a cognitive marker of AD¾compared to their non-risk counterparts. Conversely, there was no genotype-related difference in generalization performance in individuals who reported good sleep quality. CONCLUSION: These results indicate that sleep quality may be neuroprotective against genetic risk for AD. Future studies employing more rigorous methodology should investigate the mechanistic role of sleep neurophysiology in the pathogenesis and progression of AD associated with ABCA7. There is also need for the continued development of non-invasive sleep interventions tailored to racial groups with specific AD genetic risk profiles.

Impact of Computerized Cognitive Training on Default Mode Network Connectivity in Subjects at Risk for Alzheimer's Disease: A 78-week Randomized Controlled Trial. - Petrella, Jeffrey R; Michael, Andrew M; Qian, Min; Nwosu, Adaora; Sneed, Joel; Goldberg, Terry E; Devanand, Davangere P; Doraiswamy, P Murali (J Alzheimers Dis, 2023)
BACKGROUND: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer's disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks. OBJECTIVE: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks. METHODS: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks. RESULTS: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group. CONCLUSION: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might result in cognitively beneficial remodeling between the DMN and other networks in more severely impaired MCI subjects, parallel to the observed clinical benefits.
Keywords: Alzheimer Disease; Brain; Cognitive Dysfunction; Cognitive Training; Default Mode Network; Humans; Magnetic Resonance Imaging; Nerve Net

Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease. - Kobro-Flatmoen, Asgeir; Hormann, Thea Meier; Gouras, Gunnar (J Alzheimers Dis, 2023)
BACKGROUND: Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains. OBJECTIVE: To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease. METHODS: Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years. RESULTS: In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects. CONCLUSION: Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.

Klotho Gene Expression Is Decreased in Peripheral Blood Mononuclear Cells in Patients with Alzheimer's Disease and Frontotemporal Dementia. - Sorrentino, Federica; Fenoglio, Chiara; Sacchi, Luca; Serpente, Maria; Arighi, Andrea; Carandini, Tiziana; Arosio, Beatrice; Ferri, Evelyn; Arcaro, Marina; Visconte, Caterina; Rotondo, Emanuela; Scarpini, Elio; et al. (J Alzheimers Dis, 2023)
BACKGROUND: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. OBJECTIVE: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. METHODS: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. RESULTS: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, p = 0.0037). CONCLUSION: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.

Landscape of Double-Stranded DNA Breaks in Postmortem Brains from Alzheimer's Disease and Non-Demented Individuals. - Zhang, Xiaoyu; Liu, Yan; Huang, Ming; Gunewardena, Sumedha; Haeri, Mohammad; Swerdlow, Russell H; Wang, Ning (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear. OBJECTIVE: To map genome-wide DSB distributions in AD and age-matched control brains. METHODS: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing. RESULTS: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression. CONCLUSION: To our knowledge, this study is the first to characterize the AD brain DSB landscape. Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression.

Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia. - Kalia, Vrinda; Kulick, Erin R; Vardarajan, Badri; Gu, Yian; Manly, Jennifer J; Elkind, Mitchell S V; Kaufman, Joel D; Jones, Dean P; Baccarelli, Andrea A; Mayeux, Richard; Kioumourtzoglou, Marianthi-Anna; Miller, Gary W (J Alzheimers Dis, 2023)
BACKGROUND: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. OBJECTIVE: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5μm in aerodynamic diameter (PM2.5), PM less than 10μm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population. METHODS: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995-2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. RESULTS: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer's disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. CONCLUSIONS: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.
Keywords: Aged; Aging; Air Pollutants; Air Pollution; Dementia; Environmental Exposure; Humans; Nitrogen Dioxide; Particulate Matter

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease. - Chwa, Won Jong; Raji, Cyrus A; Toups, Kat; Hathaway, Ann; Gordon, Deborah; Chung, Henrianna; Boyd, Alan; Hill, Benjamin D; Hausman-Cohen, Sharon; Attarha, Mouna; Jarrett, Michael; Bredesen, Dale E (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.
Keywords: Alzheimer Disease; Atrophy; Brain; Cognitive Dysfunction; Gray Matter; Humans; Magnetic Resonance Imaging; Precision Medicine; White Matter

Medial Temporal Lobe Atrophy in Predementia Alzheimer's Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort. - Jarholm, Jonas Alexander; Bjørnerud, Atle; Dalaker, Turi Olene; Akhavi, Mehdi Sadat; Kirsebom, Bjørn Eivind; Pålhaugen, Lene; Nordengen, Kaja; Grøntvedt, Gøril Rolfseng; Nakling, Arne; Kalheim, Lisa F; Almdahl, Ina S; Tecelao, Sandra; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer's disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). OBJECTIVE: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. METHODS: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. RESULTS: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-. CONCLUSION: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.
Keywords: Alzheimer Disease; Atrophy; Cognitive Dysfunction; Entorhinal Cortex; Hippocampus; Humans; Magnetic Resonance Imaging; Temporal Lobe

Microglia-Mediated Neurovascular Unit Dysfunction in Alzheimer's Disease. - Huang, Wenhao; Xia, Qing; Zheng, Feifei; Zhao, Xue; Ge, Fangliang; Xiao, Jiaying; Liu, Zijie; Shen, Yingying; Ye, Ke; Wang, Dayong; Li, Yanze (J Alzheimers Dis, 2023)
The neurovascular unit (NVU) is involved in the pathological changes in Alzheimer's disease (AD). The NVU is a structural and functional complex that maintains microenvironmental homeostasis and metabolic balance in the central nervous system. As one of the most important components of the NVU, microglia not only induce blood-brain barrier breakdown by promoting neuroinflammation, the infiltration of peripheral white blood cells and oxidative stress but also mediate neurovascular uncoupling by inducing mitochondrial dysfunction in neurons, abnormal contraction of cerebral vessels, and pericyte loss in AD. In addition, microglia-mediated dysfunction of cellular components in the NVU, such as astrocytes and pericytes, can destroy the integrity of the NVU and lead to NVU impairment. Therefore, we review the mechanisms of microglia-mediated NVU dysfunction in AD. Furthermore, existing therapeutic advancements aimed at restoring the function of microglia and the NVU in AD are discussed. Finally, we predict the role of pericytes in microglia-mediated NVU dysfunction in AD is the hotspot in the future.
Keywords: Alzheimer Disease; Astrocytes; Blood-Brain Barrier; Humans; Microglia; Neurons

Mitochondria Profoundly Influence Apolipoprotein E Biology. - Gabrielli, Alexander P; Weidling, Ian; Ranjan, Amol; Wang, Xiaowan; Novikova, Lesya; Chowdhury, Subir Roy; Menta, Blaise; Berkowicz, Alexandra; Wilkins, Heather M; Peterson, Kenneth R; Swerdlow, Russell H (J Alzheimers Dis, 2023)
BACKGROUND: Mitochondria can trigger Alzheimer's disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known. OBJECTIVE: Consider whether and how mitochondrial biology influences APOE and apoE biology. METHODS: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression. RESULTS: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels. CONCLUSION: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.
Keywords: Alzheimer Disease; Apolipoproteins E; Biology; Cell Line, Tumor; DNA, Mitochondrial; Humans; Mitochondria; Neuroblastoma; RNA, Messenger; Transcription Factors

MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample. - Pase, Matthew P; Pinheiro, Adlin; Rowsthorn, Ella; Demissie, Serkalem; Hurmez, Saoresho; Aparicio, Hugo; Rodriguez-Lara, Frances; Gonzales, Mitzi M; Beiser, Alexa; DeCarli, Charles; Seshadri, Sudha; Romero, Jose Rafael (J Alzheimers Dis, 2023)
BACKGROUND: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. OBJECTIVE: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). METHODS: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. RESULTS: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14). CONCLUSIONS: PVS burden in the CSO may be a risk marker for early cognitive impairment.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol. - Bahrani, Ahmed A; Abner, Erin L; DeCarli, Charles S; Barber, Justin M; Sutton, Abigail C; Maillard, Pauline; Sandoval, Francisco; Arfanakis, Konstantinos; Yang, Yung-Chuan; Evia, Arnold M; Schneider, Julie A; Habes, Mohamad; et al. (J Alzheimers Dis, 2023)
BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer's Disease. - Corrigan, Rachel R; Labrador, Luis; Grizzanti, John; Mey, Megan; Piontkivska, Helen; Casadesus-Smith, Gemma (J Alzheimers Dis, 2023)
BACKGROUND: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer's disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. OBJECTIVE: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. METHODS: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. RESULTS: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. CONCLUSION: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity. - Castillo, Carolina; Bravo-Arrepol, Gastón; Wendt, Aline; Saez-Orellana, Francisco; Millar, Camila; Burgos, Carlos F; Gavilán, Javiera; Pacheco, Carla; Ahumada-Rudolph, Ramón; Napiórkowska, Mariola; Pérez, Claudia; Becerra, José; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. OBJECTIVE: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed. METHODS: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs. RESULTS: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. CONCLUSION: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Lignans; Mice; Neuroprotective Agents; PC12 Cells; Rats

Pathogenomic Signature and Aberrant Neurogenic Events in Experimental Cerebral Ischemic Stroke: A Neurotranscriptomic-Based Implication for Dementia. - Roshan, Syed Aasish; Elangovan, Gayathri; Gunaseelan, Dharani; Jayachandran, Swaminathan K; Kandasamy, Mahesh; Anusuyadevi, Muthuswamy (J Alzheimers Dis, 2023)
BACKGROUND: Cerebral ischemic stroke is caused due to neurovascular damage or thrombosis, leading to neuronal dysfunction, neuroinflammation, neurodegeneration, and regenerative failure responsible for neurological deficits and dementia. The valid therapeutic targets against cerebral stroke remain obscure. Thus, insight into neuropathomechanisms resulting from the aberrant expression of genes appears to be crucial. OBJECTIVE: In this study, we have elucidated how neurogenesis-related genes are altered in experimental stroke brains from the available transcriptome profiles in correlation with transcriptome profiles of human postmortem stroke brain tissues. METHODS: The transcriptome datasets available on the middle cerebral artery occlusion (MCAo) rat brains were obtained from the Gene Expression Omnibus, National Center for Biotechnology Information. Of the available datasets, 97 samples were subjected to the meta-analysis using the network analyst tool followed by Cytoscape-based enrichment mapping analysis. The key differentially expressed genes (DEGs) were validated and compared with transcriptome profiling of human stroke brains. RESULTS: Results revealed 939 genes are differently expressed in the brains of the MCAo rat model of stroke, in which 30 genes are key markers of neural stem cells, and regulators of neurogenic processes. Its convergence with DEGs from human stroke brains has revealed common targets. CONCLUSION: This study has established a panel of highly important DEGs to signify the potential therapeutic targets for neuroregenerative strategy against pathogenic events associated with cerebral stroke. The outcome of the findings can be translated to mitigate neuroregeneration failure seen in various neurological and metabolic disease manifestations with neurocognitive impairments.
Keywords: Animals; Brain; Dementia; Humans; Infarction, Middle Cerebral Artery; Ischemic Stroke; Neurogenesis; Rats; Stroke

The PI3K/AKT Signaling Pathway and Caspase-3 in Alzheimer's Disease: Which One Is the Beginner? - Khezri, Mohammad Rafi; Ghasemnejad-Berenji, Morteza; Moloodsouri, Donya (J Alzheimers Dis, 2023)
One of the main players in apoptosis during Alzheimer's disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer's disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer's disease.
Keywords: Alzheimer Disease; Apoptosis; Caspase 3; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications. - Bredesen, Dale E; Toups, Kat; Hathaway, Ann; Gordon, Deborah; Chung, Henrianna; Raji, Cyrus; Boyd, Alan; Hill, Benjamin D; Hausman-Cohen, Sharon; Attarha, Mouna; Chwa, Won Jong; Kurakin, Alexei; et al. (J Alzheimers Dis, 2023)
The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Humans; Neurodegenerative Diseases; Precision Medicine

Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research. - Cody, Shameka L; Miller, Gabe H; Fazeli, Pariya L; Wang, Ge; Li, Wei; Goodin, Burel R; Vance, David E (J Alzheimers Dis, 2023)
Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer's disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer's disease in PLWH.
Keywords: Aging; Alzheimer Disease; Comorbidity; HIV Infections; Humans

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging. - Short, Meghan I; Fohner, Alison E; Skjellegrind, Håvard K; Beiser, Alexa; Gonzales, Mitzi M; Satizabal, Claudia L; Austin, Thomas R; Longstreth, W T; Bis, Joshua C; Lopez, Oscar; Hveem, Kristian; Selbæk, Geir; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. OBJECTIVE: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. METHODS: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). RESULTS: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. CONCLUSIONS: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project. - Zhu, Carolyn W; Gu, Yian; Cosentino, Stephanie; Kociolek, Anton J; Hernandez, Michelle; Stern, Yaakov (J Alzheimers Dis, 2023)
BACKGROUND: Misidentification of dementia in Medicare claims is quite common. OBJECTIVE: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment. METHODS: Participants were enrolled the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. RESULTS: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant. CONCLUSIONS: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes. - Pacheco Pachado, Mayra; Casas, Ana I; Elbatreek, Mahmoud H; Nogales, Cristian; Guney, Emre; Espay, Alberto J; Schmidt, Harald H H W (J Alzheimers Dis, 2023)
Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.
Keywords: Aging; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Brain; Humans

Refining Risk for Alzheimer's Disease Among Heterozygous APOEɛ4 Carriers. - Patel, Smita; Wei, Jun; Shi, Zhuqing; Rifkin, Andrew S; Zheng, S Lilly; Gelfman, Elizabeth; Duggan, David; Helfand, Brian T; Hulick, Peter J; Xu, Jianfeng (J Alzheimers Dis, 2023)
In a large population-based cohort, we show not all heterozygous APOEɛ4 carriers are at increased risk for Alzheimer's disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS.
Keywords: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Heterozygote; Homozygote; Humans

A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer's Disease Ameliorates Functional and Cognitive Outcomes. - Roach, Jared C; Rapozo, Molly K; Hara, Junko; Glusman, Gwênlyn; Lovejoy, Jennifer; Shankle, William R; Hood, Leroy (J Alzheimers Dis, 2023)
BACKGROUND: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD). OBJECTIVE: The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. METHODS: Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. RESULTS: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. CONCLUSION: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

Risk Factors for Longer-Term Mortality in Discharged Patients with Dementia and SARS-CoV-2 Infection: A Matched Case-Control Study. - Chen, Shanquan; Cardinal, Rudolf N; Gräf, Stefan; O'Brien, John T; Underwood, Benjamin R (J Alzheimers Dis, 2023)
BACKGROUND: Persisting symptoms and increased mortality after SARS-CoV-2 infection has been described in COVID-19 survivors. OBJECTIVE: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. METHODS: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model. RESULTS: Compared to patients with dementia but without SARS-CoV-2 infection, people with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13-6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40-6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28-7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04-1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12-1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00-1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01-1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00-1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%. CONCLUSION: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.

Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits. - Smith, Gwenn S; Kuwabara, Hiroto; Yan, Haijuan; Nassery, Najlla; Yoon, Mark; Kamath, Vidya; Kraut, Michael; Gould, Neda F; Savonenko, Alena; Coughlin, Jennifer M; Lodge, Martin; Pomper, Martin G; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). OBJECTIVE: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. METHODS: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. RESULTS: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. CONCLUSIONS: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition; Cognition Disorders; Cognitive Dysfunction; Humans; Mice; Positron-Emission Tomography; Serotonin

Two-Year Changes in Physical Activity and Concurrent Changes in Cognitive Function in a Cohort of Adults with Metabolic Syndrome. - Rognoni, Teresa; Fernández-Matarrubia, Marta; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Corella, Dolores; Castañer, Olga; Martínez, J Alfredo; Alonso-Gómez, Ángel M; Gómez-Gracia, Enrique; Vioque, Jesús; Romaguera, Dora; López-Miranda, José; et al. (J Alzheimers Dis, 2023)
BACKGROUND: It has been proposed that physical activity (PA) could prevent cognitive decline. OBJECTIVE: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome. METHODS: Longitudinal observational study including 5,500 adults (mean age 65 years, SD = 5; women = 49.3%) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, Verbal Fluency Test, and Digit Span. The primary outcome was change in cognition at two-year follow-up, as measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome. RESULTS: No significant association was found between PA levels (or their changes) and changes in cognitive function, as measured by the GCS. A greater increase in PA levels was associated with a more favorable two-year change in performance on the Trail Making Test A (Q4 versus Q1: b = -2.15, 95% CI -4.25 to -0.05; p-trend = 0.024). No significant association was found for other neuropsychological test. CONCLUSION: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year follow-up, but they suggested a possible beneficial effect of PA on attentional function in older adults.

Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer's Disease. - Shinagawa, Hijiri; Ohuchi, Kazuki; Goto, Yuya; Hashimoto, Kohei; Kijima, Hideki; Maekawa, Shogo; Kurita, Hisaka; Inden, Masatoshi (J Alzheimers Dis, 2023)
Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer's disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson's disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Humans; Mice; Protein Transport; Vesicular Transport Proteins

Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer's Disease in a Community-Dwelling Multiethnic Cohort. - Stallard, Eric; Kociolek, Anton; Jin, Zhezhen; Ryu, Hyunnam; Lee, Seonjoo; Cosentino, Stephanie; Zhu, Carolyn; Gu, Yian; Fernandez, Kayri; Hernandez, Michelle; Kinosian, Bruce; Stern, Yaakov (J Alzheimers Dis, 2023)
BACKGROUND: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD. OBJECTIVES: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI). METHODS: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm. RESULTS: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up. CONCLUSION: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model. - Pontrello, Crystal G; McWhirt, Joshua M; Glabe, Charles G; Brewer, Gregory J (J Alzheimers Dis, 2022)
BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD). OBJECTIVE: To profile the progression of pathology in AD. METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. RESULTS: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

Alzheimer's Disease: Key Insights from Two Decades of Clinical Trial Failures. - Kim, C Kwon; Lee, Yin Rui; Ong, Lynnett; Gold, Michael; Kalali, Amir; Sarkar, Joydeep (J Alzheimers Dis, 2022)
Given the acknowledged lack of success in Alzheimer's disease (AD) drug development over the past two decades, the objective of this review was to derive key insights from the myriad failures to inform future drug development. A systematic and exhaustive review was performed on all failed AD compounds for dementia (interventional phase II and III clinical trials from ClinicalTrials.gov) from 2004 to the present. Starting with the initial ∼2,700 AD clinical trials, ∼550 trials met our initial criteria, from which 98 unique phase II and III compounds with various mechanisms of action met our criteria of a failed compound. The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved. Potential contributing methodological factors for the clinical trial failures were categorized into 1) insufficient evidence to initiate the pivotal trials, and 2) pivotal trial design shortcomings. Our evaluation found that rational drug development principles were not always followed for AD therapeutics development, and the question remains whether some of the failed compounds may have shown efficacy if the principles were better adhered to. Several recommendations are made for future AD therapeutic development. The whole database of the 98 failed compounds is presented in the Supplementary Material.
Keywords: Alzheimer Disease; Humans

Analysis and Identification Genetic Effect of SARS-CoV-2 Infections to Alzheimer's Disease Patients by Integrated Bioinformatics. - Wang, Fang; Xu, Jia; Xu, Shu-Jun; Guo, Jie-Jie; Wang, Feiming; Wang, Qin-Wen (J Alzheimers Dis, 2022)
BACKGROUND: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer's disease (AD). OBJECTIVE: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention. METHODS: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPI) network analysis were carried out. Hub genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions. RESULTS: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively. CONCLUSION: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients.
Keywords: Alzheimer Disease; Computational Biology; COVID-19; Databases, Genetic; Gene Expression Profiling; Humans; Protein Interaction Maps; SARS-CoV-2

Anticholinergic Drug Burden and Neurocognitive Performance in the Study of Latinos-Investigation of Neurocognitive Aging. - Posis, Alexander Ivan B; Tarraf, Wassim; Gonzalez, Kevin A; Soria-Lopez, Jose A; Léger, Gabriel C; Stickel, Ariana M; Daviglus, Martha L; Lamar, Melissa; Zeng, Donglin; González, Hector M (J Alzheimers Dis, 2022)
BACKGROUND: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. OBJECTIVE: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. METHODS: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. RESULTS: Anticholinergic use was associated with lower cognitive global cognition (β= -0.21; 95% CI [-0.36; -0.05]), learning (β= -0.27; 95% CI [-0.47; -0.07]), memory (β= -0.22; 95% CI [-0.41; -0.03]), and executive functioning (β= -0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: -0.28 [95% CI: -0.55, -0.01]; β: -0.28 [95% CI: -0.55, -0.01]; β: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3 = 3.59, F3 = 2.84, F3 = 3.88, respectively). CONCLUSION: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds. - McCarter, Stuart J; Lesnick, Timothy G; Lowe, Val J; Rabinstein, Alejandro A; Przybelski, Scott A; Algeciras-Schimnich, Alicia; Ramanan, Vijay K; Jack, Clifford R; Petersen, Ronald C; Knopman, David S; Boeve, Bradley F; Kantarci, Kejal; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. OBJECTIVE: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. METHODS: 712 participants from the Mayo Clinic Study of Aging with T2 * GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. RESULTS: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0). CONCLUSION: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Association of Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study. - Gorenflo, Maria P; Davis, Pamela B; Kendall, Ellen K; Olaker, Veronica R; Kaelber, David C; Xu, Rong (J Alzheimers Dis, 2022)
BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD. OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients. METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders. RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.8 1 [0.70,0.94], and 0.76 [0.70,0.92]. CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.

Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer's Disease. - Mathew, Sunu; WuDunn, Darrell; Mackay, Devin D; Vosmeier, Aaron; Tallman, Eileen F; Deardorff, Rachael; Harris, Alon; Farlow, Martin R; Brosch, Jared R; Gao, Sujuan; Apostolova, Liana G; Saykin, Andrew J; et al. (J Alzheimers Dis, 2022)
BACKGROUND: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. OBJECTIVE: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. METHODS: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. RESULTS: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. CONCLUSION: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden. - Baradaran, Hediyeh; Peloso, Gina M; Polak, Joseph F; Killiany, Ronald J; Ghosh, Saptaparni; DeCarli, Charles S; Thibault, Emma G; Sperling, Reisa A; Johnson, Keith A; Beiser, Alexa; Romero, Jose R; Seshadri, Sudha (J Alzheimers Dis, 2022)
BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Associations Between Vascular Risk Factor and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia. - Rundek, Tatjana; Del Brutto, Victor; Goryawala, Mohammed; Dong, Chuanhui; Agudelo, Christian; Saporta, Anita Seixas; Merritt, Stacy; Camargo, Christian; Ariko, Taylor; Loewenstein, David A; Duara, Ranjan; Haq, Ihtsham (J Alzheimers Dis, 2022)
BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (β= 0.03/year, p <  0.0001), Hispanic ethnicity (β= 0.29, p = 0.01), education (β= 0.04/year, p = 0.04), and coronary bypass surgery (β= 0.93, p = 0.02). CSO PVS only associated with age (β= 0.03/year, p <  0.01). APOE4 and amyloid-β were not associated with PVS. CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. - Frenzel, Stefan; Bis, Josh C; Gudmundsson, Elias F; O'Donnell, Adrienne; Simino, Jeannette; Yaqub, Amber; Bartz, Traci M; Brusselle, Guy G O; Bülow, Robin; DeCarli, Charles S; Ewert, Ralf; Gharib, Sina A; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

B Vitamin Supplementation Slows Cognitive Decline in Mild Cognitive Impairment Patients with Frontal Lobe Atrophy. - Gong, Xianmin; Shi, Lin; Wu, Yuanyuan; Luo, Yishan; Kwok, Timothy (J Alzheimers Dis, 2022)
BACKGROUND: The effects of B vitamins on mild cognitive impairment (MCI) patients' cognition have been mixed, suggesting the existence of moderating factors. OBJECTIVE: A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients. METHODS: In the 24-month randomized trial, 279 MCI outpatients took 500μ#x03BC;g methylcobalamin and 400μ#x03BC;g folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios. RESULTS: Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe. CONCLUSION: B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe.

Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS. - Levine, Deborah A; Gross, Alden L; Briceño, Emily M; Tilton, Nicholas; Whitney, Rachael; Han, Dehua; Giordani, Bruno J; Sussman, Jeremy B; Hayward, Rodney A; Burke, James F; Elkind, Mitchell S V; Moran, Andrew E; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. OBJECTIVE: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. METHODS: Pooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years. RESULTS: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. CONCLUSION: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

A Blood Test for Alzheimer's Disease: It's about Time or Not Ready for Prime Time? - Galasko, Douglas R; Grill, Joshua D; Lingler, Jennifer H; Heidebrink, Judith L (J Alzheimers Dis, 2022)
A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer's disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Hematologic Tests; Humans; tau Proteins

Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old. - Lachner, Christian; Day, Gregory S; Camsari, Gamze Balci; Kouri, Naomi; Ertekin-Taner, Nilufer; Boeve, Bradley F; Labuzan, Sydney A; Lucas, John A; Thompson, E Aubrey; Siddiqui, Habeeba; Crook, Julia E; Cabrera-Rodriguez, Janisse N; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate vascular and cancer contributions to dementia and neuropathology in oldest-old. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p <  0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

"Captive by the Uncertainty"-Experiences with Anticipatory Guidance for People Living with Dementia and Their Caregivers at a Specialty Dementia Clinic. - Shafir, Adi; Ritchie, Christine S; Garrett, Sarah B; Bernstein Sideman, Alissa; Naasan, Georges; Merrilees, Jennifer; Widera, Eric; Flint, Lynn; Harrison, Krista L (J Alzheimers Dis, 2022)
BACKGROUND: After a diagnosis of Alzheimer's disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic. OBJECTIVE: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic. METHODS: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance. RESULTS: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n = 6/9); caregivers had a mean age of 67 and were primarily female (n = 21/31). Participants felt they received incomplete or "hesitant" guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources. CONCLUSION: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision.
Keywords: Aged; Alzheimer Disease; Caregivers; Dementia; Female; Humans; Male; Qualitative Research; Uncertainty

Caregiver Tele-Assistance for Reduction of Emotional Distress During the COVID-19 Pandemic. Psychological Support to Caregivers of People with Dementia: The Italian Experience. - Rotondo, Emanuela; Galimberti, Daniela; Mercurio, Matteo; Giardinieri, Giulia; Forti, Sara; Vimercati, Roberto; Borracci, Vittoria; Fumagalli, Giorgio G; Pietroboni, Anna M; Carandini, Tiziana; Nobili, Alessandro; Scarpini, Elio; et al. (J Alzheimers Dis, 2022)
BACKGROUND: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers. OBJECTIVE: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown. METHODS: 50 caregivers were divided into two groups: "Caregiver-focused group" (Cg) and "Patient-focused group" (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life. RESULTS: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (p > 0.05), whereas they worsened significantly in Pg (p < 0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (p = 0.015), while they remained unchanged in Pg (p = 0.483). CONCLUSION: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.
Keywords: Aged; Aged, 80 and over; Caregiver Burden; Caregivers; COVID-19; Dementia; Female; Humans; Italy; Male; Middle Aged; Psychological Distress; Psychosocial Support Systems; Quality of Life; Surveys and Questionnaires; Telephone

Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function. - Nidadavolu, Lolita S; Feger, Danielle; Wu, Yuqiong; Grodstein, Francine; Gross, Alden L; Bennett, David A; Walston, Jeremy D; Oh, Esther S; Abadir, Peter M (J Alzheimers Dis, 2022)
BACKGROUND: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). OBJECTIVE: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. METHODS: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. RESULTS: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. CONCLUSION: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.

Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints. - Andriuta, Daniela; Si-Ahmed, Cherifa; Roussel, Martine; Constans, Jean-Marc; Makki, Malek; Aarabi, Ardalan; Basille, Damien; Andrejak, Claire; Godefroy, Olivier (J Alzheimers Dis, 2022)
BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.
Keywords: Cognition; COVID-19; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Neurocognitive Disorders; Neuropsychological Tests; Oxygen; White Matter

Clinical Utility of Cerebrospinal Fluid Aβ42 and Tau Measures in Diagnosing Mild Cognitive Impairment in Early Onset Dementia. - Hosseini, Akram A; Brown, Thomas; Mannino, Luca; Gran, Bruno; Junaid, Kehinde; Mukaetova-Ladinska, Elizabeta B (J Alzheimers Dis, 2022)
BACKGROUND: The differentiation of a preclinical or prodromal Alzheimer's disease (AD) is challenging particularly in patients with early onset Alzheimer's or related dementias (EOARD). We report our experience on diagnostic lumbar puncture to diagnose EOARD at a tertiary neurocognitive referral center in Nottingham, England from March 2018 to October 2020. OBJECTIVE: To assess amyloid-β42 (Aβ42), total tau, and Thr181-phosphorylated tau (p-tau) measurements in the cerebrospinal fluid (CSF) in patients with mild cognitive impairment (MCI) and in relation to their follow-up cognitive performance. METHODS: Thirty participants aged 32-68 years old (mean 59 years; 57% female) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, neuroradiological features (MRI, FDG-PET CT) and CSF Aβ42, total tau, and p-tau measurements. RESULTS: Patients with MCI who progressed to AD (prodromal AD) had significantly higher CSF total (797.63 pg/ml) and p-tau (82.31 pg/ml), and lower Aβ42 levels (398.94 pg/ml) in comparison to their counterparts with stable MCI (total tau 303.67 pg/ml, p-tau 43.56 pg/ml, Aβ42 873.44 pg/ml) (p <  0.01 for CSF total and p-tau measures and p <  0.0001 for CSF Aβ42 measures). None of the CSF biomarkers correlated with any of the cognitive performance measures. Principal component analysis confirmed that the clinical diagnosis of MCI secondary to AD, namely prodromal AD (as per NIA-AA criteria) in younger adults, was associated with decreased CSF Aβ42. CONCLUSION: In early onset AD, low levels of CSF Aβ42 appear to be more sensitive than total and p-tau measures in differentiating AD MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness of making an earlier diagnosis.

Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer's Disease. - Nabirotchkin, Serguei; Bouaziz, Jan; Glibert, Fabrice; Mandel, Jonas; Foucquier, Julie; Hajj, Rodolphe; Callizot, Noëlle; Cholet, Nathalie; Guedj, Mickaël; Cohen, Daniel (J Alzheimers Dis, 2022)
BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.

Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach. - Timsina, Jigyasha; Gomez-Fonseca, Duber; Wang, Lihua; Do, Anh; Western, Dan; Álvarez, Ignacio; Aguilar, Miquel; Pastor, Pau; Henson, Rachel L; Herries, Elizabeth; Xiong, Chengjie; Schindler, Suzanne E; et al. (J Alzheimers Dis, 2022)
BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r >  0.9). sTREM2 had a fair correlation (r >  0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study. - Gamble, Laura D; Parker, Sophie; Quinn, Catherine; Bennett, Holly Q; Martyr, Anthony; Sabatini, Serena; Pentecost, Claire; Collins, Rachel; Dawson, Eleanor; Hunt, Anna; Allan, Louise; Burns, Alistair; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. OBJECTIVE: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. METHODS: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the 'pre-pandemic group' (n = 312), assessed at two time points prior to the pandemic, and the 'pandemic group', assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling. RESULTS: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. CONCLUSIONS: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.
Keywords: Adaptation, Psychological; Caregivers; COVID-19; Dementia; Humans; Pandemics; Quality of Life

Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study. - Pedersen, Frederik Nørregaard; Stokholm, Lonny; Pouwer, Frans; Hass Rubin, Katrine; Peto, Tunde; Frydkjær-Olsen, Ulrik; Thykjær, Anne Suhr; Andersen, Nis; Andresen, Jens; Bek, Toke; La Cour, Morten; Heegaard, Steffen; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). OBJECTIVE: To investigate diabetes and DR as a risk marker of present and incident AD. METHODS: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. RESULTS: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53). CONCLUSION: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.
Keywords: Alzheimer Disease; Cohort Studies; Denmark; Diabetes Mellitus; Diabetic Retinopathy; Humans; Registries; Risk Factors

Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer's Disease, and Other Neurodegenerative Disorders. - Cutuli, Debora; Landolfo, Eugenia; Petrosini, Laura; Gelfo, Francesca (J Alzheimers Dis, 2022)
Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer's disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.
Keywords: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition; Disease Models, Animal; Environment; Humans; Neurodegenerative Diseases; Neuronal Plasticity

Evaluation of the Accuracy of Cognitive Screening Tests in Detecting Dementia Associated with Alzheimer's Disease: A Hierarchical Bayesian Latent Class Meta-Analysis. - Wang, Xiaonan; Li, Fengjie; Gao, Qi; Jiang, Zhen; Abudusaimaiti, Xiayidanmu; Yao, Jiangyue; Zhu, Huiping (J Alzheimers Dis, 2022)
BACKGROUND: Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are neuropsychological tests commonly used by physicians for screening cognitive dysfunction of Alzheimer's disease (AD). Due to different imperfect reference standards, the performance of MoCA and MMSE do not reach consensus. It is necessary to evaluate the consistence and differentiation of MoCA and MMSE in the absence of a gold standard for AD. OBJECTIVE: We aimed to assess the accuracy of MoCA and MMSE in screening AD without a gold standard reference test. METHODS: Studies were identified from PubMed, Web of Science, CNKI, Chinese Wanfang Database, China Science and Technology Journal Database, and Cochrane Library. Our search was limited to studies published in English and Chinese before August 2021. A hierarchical Bayesian latent class model was performed in meta-analysis when the gold standard was absent. RESULTS: A total of 67 studies comprising 5,554 individuals evaluated for MoCA and 76,862 for MMSE were included in this meta-analysis. The pooled sensitivity was 0.934 (95% CI 0.905 to 0.954) for MoCA and 0.883 (95% CI 0.859 to 0.903) for MMSE, while the pooled specificity was 0.899 (95% CI 0.859 to 0.928) for MoCA and 0.903 (95% CI 0.879 to 0.923) for MMSE. MoCA was useful to rule out dementia associated with AD with lower negative likelihood ratio (LR-) (0.074, 95% CI 0.051 to 0.108). MoCA showed better performance with higher diagnostic odds ratio (DOR) (124.903, 95% CI 67.459 to 231.260). CONCLUSION: MoCA had better performance than MMSE in screening dementia associated with AD from patients with mild cognitive impairment or healthy controls.
Keywords: Alzheimer Disease; Bayes Theorem; Cognition; Cognitive Dysfunction; Humans; Mental Status and Dementia Tests; Neuropsychological Tests

Expression Changes in Mitochondrial Genes Affecting Mitochondrial Morphology, Transmembrane Potential, Fragmentation, Amyloidosis, and Neuronal Cell Death Found in Brains of Alzheimer's Disease Patients. - Castora, Frank J; Kerns, Kimberly A; Pflanzer, Haley K; Hitefield, Naomi L; Gershon, Blake; Shugoll, Jason; Shelton, Morgan; Coleman, Randolph A (J Alzheimers Dis, 2022)
BACKGROUND: Alzheimer's disease (AD) is a neurological disease that has both a genetic and non-genetic origin. Mitochondrial dysfunction is a critical component in the pathogenesis of AD as deficits in oxidative capacity and energy production have been reported. OBJECTIVE: Nuclear-encoded mitochondrial genes were studied in order to understand the effects of mitochondrial expression changes on mitochondrial function in AD brains. These expression data were to be incorporated into a testable mathematical model for AD used to further assess the genes of interest as therapeutic targets for AD. METHODS: RT2-PCR arrays were used to assess expression of 84 genes involved in mitochondrial biogenesis in AD brains. A subset of mitochondrial genes of interest was identified after extensive Ingenuity Pathway Analysis (IPA) (Qiagen). Further filtering of this subset of genes of interest was achieved by individual qPCR analyses. Expression values from this group of genes were included in a mathematical model being developed to identify potential therapeutic targets. RESULTS: Nine genes involved in trafficking proteins to mitochondria, morphology of mitochondria, maintenance of mitochondrial transmembrane potential, fragmentation of mitochondria and mitochondrial dysfunction, amyloidosis, and neuronal cell death were identified as significant to the changes seen. These genes include TP53, SOD2, CDKN2A, MFN2, DNM1L, OPA1, FIS1, BNIP3, and GAPDH. CONCLUSION: Altered mitochondrial gene expression indicates that a subset of nuclear-encoded mitochondrial genes compromise multiple aspects of mitochondrial function in AD brains. A new mathematical modeling system may provide further insights into potential therapeutic targets.

Frontal Atrophy and Executive Dysfunction Relate to Complex Numbers Impairment in Progressive Supranuclear Palsy. - Howard, Erica; Ballinger, Samantha; Kinney, Nikolas G; Balgenorth, Yvonne; Ehrhardt, Annabess; Phillips, Jeffrey S; Irwin, David J; Grossman, Murray; Cousins, Katheryn A Q (J Alzheimers Dis, 2022)
BACKGROUND: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS. OBJECTIVE: To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD). METHODS: Fifty-six patients (LBSD = 35; PSP = 21) completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman's and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls. RESULTS: PSP had worse complex numbers performance than LBSD (F = 6.06, p = 0.02) but similar basic numbers performance (F = 0.38, p >  0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p = 0.01) but not JOLO (rho = 0.23, p >  0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance. CONCLUSION: PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy.

Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia. - Gentreau, Mélissa; Reynes, Christelle; Sabatier, Robert; Maller, Jerome J; Meslin, Chantal; Deverdun, Jeremy; Le Bars, Emmanuelle; Raymond, Michel; Berticat, Claire; Artero, Sylvaine (J Alzheimers Dis, 2022)
BACKGROUND: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated. OBJECTIVE: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia. METHODS: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm. RESULTS: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes. CONCLUSION: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations. - Sturchio, Andrea; Dwivedi, Alok K; Malm, Tarja; Wood, Matthew J A; Cilia, Roberto; Sharma, Jennifer S; Hill, Emily J; Schneider, Lon S; Graff-Radford, Neill R; Mori, Hiroshi; Nübling, Georg; El Andaloussi, Samir; et al. (J Alzheimers Dis, 2022)
BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8% ) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

Impact of COVID-19 on 'Living Well' with Mild-to-Moderate Dementia in the Community: Findings from the IDEAL Cohort. - Clare, Linda; Martyr, Anthony; Gamble, Laura D; Pentecost, Claire; Collins, Rachel; Dawson, Eleanor; Hunt, Anna; Parker, Sophie; Allan, Louise; Burns, Alistair; Hillman, Alexandra; Litherland, Rachael; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic. OBJECTIVE: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data. METHODS: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data. RESULTS: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to 'live well'. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics. CONCLUSION: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.
Keywords: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Caregivers; COVID-19; Dementia; Female; Humans; Male; Middle Aged; Neighborhood Characteristics; Quality of Life; SARS-CoV-2

Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study. - Laton, Jorne; Van Schependom, Jeroen; Goossens, Joery; Wiels, Wietse; Sieben, Anne; De Deyn, Peter Paul; Goeman, Johan; Streffer, Johannes; van der Zee, Julie; Martin, Jean-Jacques; Van Broeckhoven, Christine; De Vos, Maarten; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease. - Green, Zachary D; Vidoni, Eric D; Swerdlow, Russell H; Burns, Jeffrey M; Morris, Jill K; Honea, Robyn A (J Alzheimers Dis, 2022)
BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

Informal Caregivers' Attitude Toward Dementia: The Impact of Dementia Knowledge, Confidence in Dementia Care, and the Behavioral and Psychological Symptoms of the Person with Dementia. A Cross-Sectional Study. - Teichmann, Birgit; Gkioka, Mara; Kruse, Andreas; Tsolaki, Magda (J Alzheimers Dis, 2022)
BACKGROUND: Dementia is rapidly increasing worldwide due to demographic aging. More than two-thirds of patients are cared by family members. The quality of care depends on the caregivers' attitude toward dementia influencing patient care decisions. OBJECTIVE: The aim of this study is to examine the factors that influence the caregivers' attitude and whether there is an association between participation in a psycho-educational program and attitude. METHODS: We performed a cross-sectional study using a structured closed-ended questionnaire to retrieve socio-demographic information from caregivers and the persons with dementia (N = 86). The study included validated scales such as the Dementia Attitude Scale, the Dementia Knowledge Assessment Tool 2, the Positive Aspects of Caregiving, the Zarit Burden Interview, the Confidence in Dementia Scale, and Spielberger's State-Trait Anxiety Inventory, as well as a neuropsychological battery to assess the condition of people with dementia. RESULTS: Our final model explains 55.6% of the total variance and shows a significant correlation of five factors with attitude toward dementia: confidence, behavioral and psychological symptoms of dementia, anxiety as a trait, positive aspects of caregiving, and dementia knowledge. The caregivers who participated in a psycho-educational program showed a significantly more positive attitude toward dementia, better dementia knowledge, higher confidence in dementia care, and lower anxiety as a state. CONCLUSION: The strong correlation of attitude and knowledge, as well as confidence in dementia care, supports the tripartite model of attitude, which hypothesizes the interrelation of affect, cognition, and behavior.
Keywords: Attitude; Caregivers; Cross-Sectional Studies; Dementia; Humans; Surveys and Questionnaires

Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults. - Wittfeld, Katharina; Raman, Mekala R; Conner, Sarah C; Aslam, Asra; Teumer, Alexander; Nauck, Matthias; Hosten, Norbert; Habes, Mohamad; DeCarli, Charles; Vasan, Ramachandran S; Beiser, Alexa S; Himali, Jayandra J; et al. (J Alzheimers Dis, 2022)
BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

Late-Onset Alcohol Abuse as a Presenting Symptom of Neurodegenerative Diseases. - de Paula França Resende, Elisa; Ketelle, Robin; Karydas, Anna; Allen, Isabel; Grinberg, Lea T; Spina, Salvatore; Seeley, William W; Perry, David C; Miller, Bruce; Naasan, Georges (J Alzheimers Dis, 2022)
BACKGROUND: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease. OBJECTIVE: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases. METHODS: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) (n = 1,518). The presence of alcohol abuse was screened with the National Alzheimer's Coordinating Center questionnaire. L-AA was defined as onset <  40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset. RESULTS: The frequency of LO-AA was 2.2% (n = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n = 13/173 versus 1.3%, n = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n = 4/91, CI: -4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n = 10/173 versus 0.7%, n = 9/1,254, CI:0.5% ;9.5%), but not svPPA (2.2%, n = 2/91, CI:-2.4;9.1%). CONCLUSION: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study.

Lipid Peroxidation as a Marker of Apathy and Executive Dysfunction in Patients at Risk for Vascular Cognitive Impairment. - Bawa, Kritleen K; Ba, Joycelyn; Kiss, Alex; Wang, RuoDing; Feng, Vivian; Swardfager, Walter; Andreazza, Ana; Gallagher, Damien; Marotta, Giovanni; Herrmann, Nathan; Lanctôt, Krista L (J Alzheimers Dis, 2022)
BACKGROUND: The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown. OBJECTIVE: This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI. METHODS: In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated. RESULTS: Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p <  0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p <  0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002). CONCLUSION: The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI.

Low-Dose Radiation Therapy Reduces Amyloid Load in Young 3xTg-AD Mice. - Ceyzériat, Kelly; Tournier, Benjamin B; Millet, Philippe; Dipasquale, Giovanna; Koutsouvelis, Nikolaos; Frisoni, Giovanni B; Garibotto, Valentina; Zilli, Thomas (J Alzheimers Dis, 2022)
BACKGROUND: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer's disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood. OBJECTIVE: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated. METHODS: The whole brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA. RESULTS: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aβ 42 aggregated forms (-71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed. CONCLUSION: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies.

Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign. - Josephs, Kennedy A; Pham, Nha Trang Thu; Graff-Radford, Jonathan; Machulda, Mary M; Lowe, Val J; Whitwell, Jennifer L (J Alzheimers Dis, 2022)
BACKGROUND: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). OBJECTIVE: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. METHODS: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. RESULTS: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. CONCLUSION: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.
Keywords: Alzheimer Disease; Atrophy; Fluorodeoxyglucose F18; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Positron-Emission Tomography

Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods. - Beheshti, Iman; Geddert, Natasha; Perron, Jarrad; Gupta, Vinay; Albensi, Benedict C; Ko, Ji Hyun (J Alzheimers Dis, 2022)
BACKGROUND: We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. OBJECTIVE: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. METHODS: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. RESULTS: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p <  0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q <  0.01). CONCLUSION: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. - Weinstein, Galit; O'Donnell, Adrienne; Davis-Plourde, Kendra; Zelber-Sagi, Shira; Ghosh, Saptaparni; DeCarli, Charles S; Thibault, Emma G; Sperling, Reisa A; Johnson, Keith A; Beiser, Alexa S; Seshadri, Sudha (J Alzheimers Dis, 2022)
BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 >  1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p <  0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p <  0.001; β= 1.59±0.38, p <  0.001, and β= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer's Disease. - Araújo, Daniella Castro; Veloso, Adriano Alonso; Gomes, Karina Braga; de Souza, Leonardo Cruz; Ziviani, Nivio; Caramelli, Paulo (J Alzheimers Dis, 2022)
BACKGROUND: A cheap and minimum-invasive method for early identification of Alzheimer's disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease. OBJECTIVE: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon. METHODS: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer's Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia. RESULTS: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years. CONCLUSION: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.

The Outcome of Patients with Amyloid-Negative Amnestic Mild Cognitive Impairment. - Cardoso, Sandra; Silva, Dina; Alves, Luísa; Guerreiro, Manuela; Mendonça, Alexandre de (J Alzheimers Dis, 2022)
BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer's disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear. OBJECTIVE: To know the etiology and prognosis of amyloid-negative aMCI. METHODS: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments. RESULTS: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease. CONCLUSION: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised.

Peptidylarginine Deiminase and Alzheimer's Disease. - Wang, Lai; Chen, Hongyang; Tang, Jing; Guo, Zhengwei; Wang, Yanming (J Alzheimers Dis, 2022)
Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer's disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.
Keywords: Alzheimer Disease; Animals; Cerebral Cortex; Citrulline; Hippocampus; Humans; Isoenzymes; Protein Processing, Post-Translational; Protein-Arginine Deiminases

Polygenic Scores of Alzheimer's Disease Risk Genes Add Only Modestly to APOE in Explaining Variation in Amyloid PET Burden. - Ramanan, Vijay K; Heckman, Michael G; Przybelski, Scott A; Lesnick, Timothy G; Lowe, Val J; Graff-Radford, Jonathan; Mielke, M; Jack, Clifford R; Knopman, David S; Petersen, Ronald C; Ross, Owen A; Vemuri, Prashanthi (J Alzheimers Dis, 2022)
BACKGROUND: Brain accumulation of amyloid-β is a hallmark event in Alzheimer's disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. OBJECTIVE: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. RESULTS: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p = 1.51×10-50) and ADNI (p = 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. CONCLUSION: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project. - Toups, Kat; Hathaway, Ann; Gordon, Deborah; Chung, Henrianna; Raji, Cyrus; Boyd, Alan; Hill, Benjamin D; Hausman-Cohen, Sharon; Attarha, Mouna; Chwa, Won Jong; Jarrett, Michael; Bredesen, Dale E (J Alzheimers Dis, 2022)
BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study. - Loreto, Flavia; Fitzgerald, Anna; Golemme, Mara; Gunning, Stephen; Win, Zarni; Patel, Neva; Carswell, Christopher; Perry, Richard; Kennedy, Angus; Edison, Paul; Malhotra, Paresh (J Alzheimers Dis, 2022)
BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET had a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. - Agüera-Ortiz, Luis; Babulal, Ganesh M; Bruneau, Marie-Andrée; Creese, Byron; D'Antonio, Fabrizia; Fischer, Corinne E; Gatchel, Jennifer R; Ismail, Zahinoor; Kumar, Sanjeev; McGeown, William J; Mortby, Moyra E; Nuñez, Nicolas A; et al. (J Alzheimers Dis, 2022)
Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.
Keywords: Caregivers; Dementia; Hallucinations; Humans; Psychotic Disorders; Schizophrenia

Relationship Between the Gut Microbiota and Alzheimer's Disease: A Systematic Review. - González Cordero, Elisa Marina; Cuevas-Budhart, Miguel Angel; Pérez Morán, Diana; Trejo Villeda, Miguel Angel; Gomez-Del-Pulgar Gª-Madrid, Mercedes (J Alzheimers Dis, 2022)
BACKGROUND: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated. OBJECTIVE: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer's disease. METHOD: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish. RESULTS: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review. CONCLUSION: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.
Keywords: Alzheimer Disease; Brain; Brain-Gut Axis; Cognitive Dysfunction; Gastrointestinal Microbiome; Humans

Relationship Between Weight-Change Patterns and Cognitive Function: A Retrospective Study. - Gong, Hong-Jian; Tang, Xingyao; Chai, Yin-He; Qiao, Yu-Shun; Xu, Hui; Patel, Ikramulhaq; Zhang, Jin-Yan; Simó, Rafael; Zhou, Jian-Bo (J Alzheimers Dis, 2022)
BACKGROUND: Obesity has been linked to cognitive impairment. However, how changes in body mass index (BMI) over the life course influence cognitive function remains unclear. OBJECTIVE: The influence of distinct weight-change patterns from young adulthood to midlife and late adulthood on cognitive function in older adults was explored. METHODS: A total of 5,809 individuals aged≥60 years were included and categorized into four groups on the basis of BMI change patterns. Cognitive function was assessed using four cognition tests in the baseline survey. The relationship between the weight-change patterns and cognition was evaluated using regression models. RESULTS: In comparison with participants who remained at non-obese, those moving from the non-obese to obese weight-change pattern from young (25 years of age) to middle adulthood showed lower Digit Symbol Substitution Test (DSST) scores (β= -1.28; 95% confidence interval [CI]: -2.24 to -0.32). A non-obese to obese change pattern from age 25 years of age to 10 years before baseline was associated with a higher risk of DSST impairment (odds ratio = 1.40; 95% CI: 1.09 to 1.79). In comparison with participants whose heaviest weight was recorded after 60 years of age, those with the heaviest weight between 18 and 40 years of age had lower DSST scores (β= -1.46; 95% CI: -2.77 to -1.52). CONCLUSION: Our results suggest that the transition from the non-obese to obese category in early adulthood and appearance of the heaviest weight between 18 and 40 years of age are associated with lower cognitive function in later life.

The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer's Disease Risks. - Kim, Hyun; Levine, Alina; Cohen, Daniel; Gehrman, Philip; Zhu, Xi; Devanand, Davangere P; Lee, Seonjoo; Goldberg, Terry E (J Alzheimers Dis, 2022)
BACKGROUND: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. OBJECTIVE: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline. METHODS: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models. RESULTS: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition. CONCLUSION: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals. - Walker, Jamie M; Dehkordi, Shiva Kazempour; Schaffert, Jeff; Goette, William; White Iii, Charles L; Richardson, Timothy E; Zare, Habil (J Alzheimers Dis, 2022)
BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-β (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).

Alzheimer's Disease and Face Masks in Times of COVID-19. - Gil, Roger; Arroyo-Anlló, Eva M (J Alzheimers Dis, 2021)
Generalized lockdown caused by COVID-19, necessary yesterday, can no longer be that of tomorrow. It will no longer be possible to cram the humblest into cramped areas, but priority must be given to prevention (certainly with physical barriers, hydro-alcoholic gel, face masks), biological diagnosis, isolation, and also the care of any infected person. COVID-19 has hit the most vulnerable first in terms of biological inequality, such as Alzheimer's disease (AD) patients. Those with AD can have sensorial deficits and perception troubles, including visual difficulties and the inability to recognize faces and emotions. Face masks and physical distancing can disrupt facial familiarity and make it more difficult to recognize emotional facial expressions. It can provoke distress, which the visitor can perceive and feel obligated to take off the face mask. This gesture should not be considered as an act of indiscipline, but an act of empathy. Transparent face masks could improve the suffering of AD patients, distraught in the presence of their loved ones whose masks hide their faces. Wearing a mask should not be due to fear of punishment, but as an understanding of the responsibility of each individual in the control of the current pandemic. It may be necessary to convince more citizens of this civic duty, using clear and attractive messaging in order to standardize the wearing of face masks for the general public and to adapt them to the needs of patients.
Keywords: Alzheimer Disease; Communicable Disease Control; COVID-19; Emotions; Facial Expression; Humans; Masks

Alzheimer's Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort. - Barthold, Douglas; Gibbons, Laura E; Marcum, Zachary A; Gray, Shelly L; Dirk Keene, C; Grabowski, Thomas J; Postupna, Nadia; Larson, Eric B; Crane, Paul K (J Alzheimers Dis, 2021)
BACKGROUND: Diabetes is a risk factor for Alzheimer's disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). OBJECTIVE: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. METHODS: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. RESULTS: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively). CONCLUSION: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Association of Malnutrition with Functional and Cognitive Trajectories in People Living with Dementia: A Five-Year Follow-Up Study. - Borda, Miguel Germán; Ayala Copete, Ana María; Tovar-Rios, Diego Alejandro; Jaramillo-Jimenez, Alberto; Giil, Lasse Melvær; Soennesyn, Hogne; Gómez-Arteaga, Camilo; Venegas-Sanabria, Luis Carlos; Kristiansen, Ida; Chavarro-Carvajal, Diego Andrés; Caicedo, Sandra; Cano-Gutierrez, Carlos Alberto; et al. (J Alzheimers Dis, 2021)
BACKGROUND: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. OBJECTIVE: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. METHODS: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer's disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. RESULTS: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. CONCLUSION: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study. - Gonzales, Mitzi M; Samra, Jasmeet; O'Donnell, Adrienne; Mackin, R Scott; Salinas, Joel; Jacob, Mini; Satizabal, Claudia L; Aparicio, Hugo J; Thibault, Emma G; Sanchez, Justin S; Finney, Rebecca; Rubinstein, Zoe B; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012). CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation. - Dekker, Alain D; Ulgiati, Aurora M; Groen, Henk; Boxelaar, Vincent A; Sacco, Silvia; Falquero, Ségolène; Carfi, Angelo; di Paola, Antonella; Benejam, Bessy; Valldeneu, Silvia; Fopma, Roelie; Oosterik, Marjo; et al. (J Alzheimers Dis, 2021)
BACKGROUND: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. OBJECTIVE: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. METHODS: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113). RESULTS: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. CONCLUSION: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.
Keywords: Adult; Aged; Anxiety; Dementia; Down Syndrome; Female; Humans; Irritable Mood; Male; Middle Aged; Reproducibility of Results; Symptom Assessment

Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer's Disease Brain Tissues. - Senejani, Alireza G; Maghsoudlou, Jasmin; El-Zohiry, Dina; Gaur, Gauri; Wawrzeniak, Keith; Caravaglia, Cristina; Khatri, Vishwa A; MacDonald, Alan; Sapi, Eva (J Alzheimers Dis, 2021)
BACKGROUND: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. OBJECTIVE: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer's (AD) or Parkinson's diseases. METHODS: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods. RESULTS: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and anti-phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-β and p-Tau proteins in both cells lines post-infection. CONCLUSION: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.

Central Obesity, Cardiometabolic Risk, and Cognitive Change in the Study of Latinos: Investigation of Neurocognitive Aging. - Stickel, Ariana M; Tarraf, Wassim; Gonzalez, Kevin A; Isasi, Carmen R; Kaplan, Robert; Gallo, Linda C; Zeng, Donglin; Cai, Jianwen; Pirzada, Amber; Daviglus, Martha L; Goodman, Zachary T; Schneiderman, Neil; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The relationships between obesity and cognitive decline in aging are mixed and understudied among Hispanics/Latinos. OBJECTIVE: To understand associations between central obesity, cognitive aging, and the role of concomitant cardiometabolic abnormalities among Hispanics/Latinos. METHODS: Participants included 6,377 diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation for Neurocognitive Aging (SOL-INCA). Participants were 45 years and older at the first cognitive testing session (Visit 1). Cognitive outcomes (z-score units) included global composite and domain specific (learning, memory, executive functioning, processing speed) measures at a second visit (SOL-INCA, on average, 7 years later), and 7-year change. We used survey linear regression to examine associations between central obesity (waist circumference≥88 cm and≥102 cm for women and men, respectively) and cognition. We also tested whether the relationships between obesity and cognition differed by cardiometabolic status (indication of/treatment for 2 + of the following: high triglycerides, hypertension, hyperglycemia, low high-density lipoprotein cholesterol). RESULTS: Central obesity was largely unassociated with cognitive outcomes, adjusting for covariates. However, among individuals with central obesity, cardiometabolic abnormality was linked to poorer cognitive function at SOL-INCA (ΔGlobalCognition =-0.165, p < 0.001) and to more pronounced cognitive declines over the average 7 years (ΔGlobalCognition = -0.109, p < 0.05); this was consistent across cognitive domains. CONCLUSION: Central obesity alone was not associated with cognitive function. However, presence of both central obesity and cardiometabolic abnormalities was robustly predictive of cognition and 7-year cognitive declines, suggesting that in combination these factors may alter the cognitive trajectories of middle-aged and older Hispanics/Latinos.

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction. - VanDusen, Keith W; Li, Yi-Ju; Cai, Victor; Hall, Ashley; Hiles, Sarah; Thompson, J Will; Moseley, M Arthur; Cooter, Mary; Acker, Leah; Levy, Jerrold H; Ghadimi, Kamrouz; Quiñones, Quintin J; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13). CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. - Ryman, Sephira G; Yutsis, Maya; Tian, Lu; Henderson, Victor W; Montine, Thomas J; Salmon, David P; Galasko, Douglas; Poston, Kathleen L (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology. OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD. METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical). RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage. CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cognitive Dysfunction; Female; Humans; Lewy Body Disease; Male

Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial. - Cummings, Jeffrey; Schwartz, Gregory G; Nicholls, Stephen J; Khan, Aziz; Halliday, Chris; Toth, Peter P; Sweeney, Michael; Johansson, Jan O; Wong, Norman C W; Kulikowski, Ewelina; Kalantar-Zadeh, Kamyar; Lebioda, Kenneth; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. OBJECTIVE: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). METHODS: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. RESULTS: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). CONCLUSION: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
Keywords: Aged; Cardiovascular Diseases; Cognitive Dysfunction; Epigenesis, Genetic; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Quinazolinones

Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology. - Squitti, Rosanna; Faller, Peter; Hureau, Christelle; Granzotto, Alberto; White, Anthony R; Kepp, Kasper P (J Alzheimers Dis, 2021)
The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.

A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project. - Wimo, Anders; Belger, Mark; Bon, Jaka; Jessen, Frank; Dumas, Annette; Kramberger, Milica G; Jamilis, Laura; Johansson, Gunilla; Rodrigo Salas, Adrián; Rodríguez Gómez, Octavio; Sannemann, Lena; Stoekenbroek, Malou; et al. (J Alzheimers Dis, 2021)
BACKGROUND: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. OBJECTIVE: To make a cost-consequence analysis of MOPEAD. METHODS: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population. RESULTS: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was 3,115€ with the web-approach, 2,722€ with the Open-House, 1,530€ in primary care, and 1,190€ by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. CONCLUSION: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

COVID-19: Association Between Increase of Behavioral and Psychological Symptoms of Dementia During Lockdown and Caregivers' Poor Mental Health. - Pongan, Elodie; Dorey, Jean-Michel; Borg, Céline; Getenet, Jean Claude; Bachelet, Romain; Lourioux, Charles; Laurent, Bernard; Rey, Romain; Rouch, Isabelle (J Alzheimers Dis, 2021)
BACKGROUND: From March 2020, the support and care systems for caregivers and people with dementia (PWD) were suspended or dramatically changed due to the lockdown during the world pandemic of COVID-19. Thus, these changes in living conditions have had deleterious consequences on the behavior of PWD and subsequently on their caregivers' mental health, the two being linked. OBJECTIVE: Our study aimed to examine changes in behavior among PWD and to look for associations between the evolution of behavioral and psychological symptoms of dementia (BPSD) and caregivers' mental health in the context of COVID-19. METHODS: The study was conducted among caregivers of PWD living at home in France. Caregivers were interviewed via an anonymous cross-sectional online survey during the first lockdown between April 15 and June 15, 2020. RESULTS: Three hundred and eighty-nine caregivers accompanying a relative living at home participated in the study; 43.3%of the PWD presented a worsening of BPSD during the lockdown. With multivariate logistic regressions, a significant association was observed between "more BPSD" and burden, anxiety and depression, between "BPSD equivalent" and anxiety and depression, and between "emerging BPSD" and only depression. CONCLUSION: The lockdown seems to have an impact on behavioral disorders in PWD and these disorders are associated with poorer mental health of caregivers. Our findings suggest attention should be given to caregivers of PWD who have BPSD before lockdown and the need for continued consultations and professional help in case of new lockdowns.
Keywords: Aged; Aged, 80 and over; Caregivers; Communicable Disease Control; COVID-19; Cross-Sectional Studies; Dementia; Female; France; Humans; Male; Mental Disorders; Mental Health; Middle Aged; Surveys and Questionnaires

Current and Future Prevalence Estimates of Mild Cognitive Impairment, Dementia, and Its Subtypes in a Population-Based Sample of People 70 Years and Older in Norway: The HUNT Study. - GjØra, Linda; Strand, Bjørn Heine; Bergh, Sverre; Borza, Tom; Brækhus, Anne; Engedal, Knut; Johannessen, Aud; Kvello-Alme, Marte; Krokstad, Steinar; Livingston, Gill; Matthews, Fiona E; Myrstad, Christian; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative. OBJECTIVE: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study. METHODS: All people 70 + years of age, n = 19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70 + . Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness. RESULTS: A total of 9,930 (51.2%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9-15.4) and 35.3% (95% CI 34.3-36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer's disease (57%). By adding data collected from a study of persons < 70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively. CONCLUSION: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Dementia; Female; Forecasting; Humans; Male; Mental Status and Dementia Tests; Neuropsychological Tests; Norway; Prevalence; Sex Factors; Surveys and Questionnaires

Current Status and Challenges of Stem Cell Treatment for Alzheimer's Disease. - Pacheco-Herrero, Mar; Soto-Rojas, Luis O; Reyes-Sabater, Heidy; Garcés-Ramirez, Linda; de la Cruz López, Fidel; Villanueva-Fierro, Ignacio; Luna-Muñoz, José (J Alzheimers Dis, 2021)
Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.
Keywords: Alzheimer Disease; Amyloid; Government Regulation; Hippocampus; Humans; Neocortex; Neurofibrillary Tangles; Plaque, Amyloid; Stem Cells; tau Proteins

Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care. - Toniolo, Sofia; Scarioni, Marta; Di Lorenzo, Francesco; Hort, Jakub; Georges, Jean; Tomic, Svetlana; Nobili, Flavio; Frederiksen, Kristian Steen (J Alzheimers Dis, 2021)
Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.
Keywords: Alzheimer Disease; Biomarkers; Brain; Cognitive Dysfunction; Comorbidity; COVID-19; Humans; Neuroimaging; Neuroimmunomodulation; Patient Care; SARS-CoV-2

Depression and Dementia: The Role of Cortisol and Vascular Brain Lesions. AGES-Reykjavik Study. - Gerritsen, Lotte; Twait, Emma L; Jonsson, Palmi V; Gudnason, Vilmundur; Launer, Lenore J; Geerlings, Mirjam I (J Alzheimers Dis, 2021)
BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08). CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline. - Brenowitz, Willa D; Zeki Al Hazzouri, Adina; Vittinghoff, Eric; Golden, Sherita H; Fitzpatrick, Annette L; Yaffe, Kristine (J Alzheimers Dis, 2021)
BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited. OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline. METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score. RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p <  0.05). CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods. - Devlin, Kathryn N; Brennan, Laura; Saad, Laura; Giovannetti, Tania; Hamilton, Roy H; Wolk, David A; Xie, Sharon X; Mechanic-Hamilton, Dawn (J Alzheimers Dis, 2021)
BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators among diverse older adults. METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

Diet May Moderate the Relationship Between Arterial Stiffness and Cognitive Performance in Older Adults. - Gauci, Sarah; Young, Lauren M; White, David J; Reddan, Jeffery M; Lassemillante, Annie-Claude; Meyer, Denny; Pipingas, Andrew; Scholey, Andrew (J Alzheimers Dis, 2021)
BACKGROUND: Cognitive decline is influenced by various factors including diet, cardiovascular disease, and glucose control. However, the combined effect of these risk factors on cognitive performance is yet to be fully understood. OBJECTIVE: The current study aimed to explore the inter-relationship between these risk factors and cognitive performance in older adults at risk of future cognitive decline. METHODS: The sample comprised 163 (Age: M = 65.23 years, SD = 6.50) participants. Food Frequency Questionnaire data was used to score diet quality and adherence to the Western Style Diet (WSD) and Prudent Style Diet (PSD). Glucose control was gauged by serum levels of glycated hemoglobin (HbA1c) and arterial stiffness was measured using carotid to femoral pulse wave velocity. Cognitive performance was assessed using two subtests of the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) and Rey's Verbal Learning Test (RVLT). RESULTS: Diet quality, adherence to the WSD or PSD, and glucose control were not significantly related to cognitive outcomes. However, a significant negative association was found between arterial stiffness and the spatial working memory subtest of SUCCAB (β= -0.21, p <  0.05). Arterial stiffness also significantly interacted with the PSD to impact total recall (F change (1,134) = 5.37, p <  0.05) and the composite score of RVLT (F change (1,134) = 4.03, p <  0.05). CONCLUSION: In this sample of older adults at risk of cognitive decline, diet alone was not found to predict cognitive performance; however, it was found to moderate the relationship between arterial stiffness and cognition.

Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid. - Boström, Gustaf; Freyhult, Eva; Virhammar, Johan; Alcolea, Daniel; Tumani, Hayrettin; Otto, Markus; Brundin, Rose-Marie; Kilander, Lena; Löwenmark, Malin; Giedraitis, Vilmantas; Lleo, Alberto; von Arnim, Christine A F; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Female; Frontotemporal Dementia; Humans; Inflammation; Male; Middle Aged; Peptide Fragments; tau Proteins

Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer's Disease. - Soldevila-Domenech, Natalia; Forcano, Laura; Boronat, Anna; Lorenzo, Thais; Piera, Iris; Puig-Pijoan, Albert; Mateus, Julian; González de Echevarri Gómez, José María; Knezevic, Iva; Soteras, Anna; Fauria, Karine; Pizarro, Nieves; et al. (J Alzheimers Dis, 2021)
We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Anxiety Disorders; Apolipoprotein E3; Apolipoprotein E4; Cognition Disorders; Cognitive Dysfunction; COVID-19; Depressive Disorder; Female; Humans; Male; Mental Health; Middle Aged; Psychological Distress; Quarantine; Risk; Spain

Effects of High Definition-Transcranial Direct Current Stimulation on Local GABA and Glutamate Levels Among Older Adults with and without Mild Cognitive Impairment: An Exploratory Study. - Lengu, Ketrin; Ryan, Shannon; Peltier, Scott J; Tyszkowski, Troy; Kairys, Anson; Giordani, Bruno; Hampstead, Benjamin M (J Alzheimers Dis, 2021)
BACKGROUND: Prior research, primarily with young adults, suggests transcranial direct current stimulation (tDCS) effects are driven by the primary excitatory and/or inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA), respectively. OBJECTIVE: We examined the neurometabolic mechanisms of tDCS in older adults with and without mild cognitive impairment (MCI). METHODS: We used data from a double-blind, cross-over, randomized controlled trial (NCT01958437) in 32 older adults to evaluate high definition (HD)-tDCS-induced changes in glutamate and GABA via magnetic resonance spectroscopy (MRS). Participants underwent MRS following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right superior parietal cortex (center anode at P2) and delivered 2mA for 20 minutes. RESULTS: Relative to sham, and when co-varying for MRS voxel overlap and right superior parietal volume, active HD-tDCS significantly increased GABA and decreased the ratio of glutamate to GABA. No changes were observed in a left prefrontal control MRS voxel. Although we did not find a significant correlation between strength of delivered current (measured via MRI-based computational modeling) and neurometabolite change, there was a robust positive relationship between the volume of right superior parietal cortex and neurometabolite change. CONCLUSION: Our preliminary findings of increased GABA and reduced glutamate/GABA ratio raise the possibility that (HD-)tDCS effects differ by age. Moreover, age- and disease-related regional brain volume loss may be especially important to consider when planning future studies. Replication would emphasize the importance of developing population-specific tDCS parameters that consider structural and physiologic changes associated with "normal" and pathological aging.

Enhancing the Sensitivity of Memory Tests: Reference Data for the Free and Cued Selective Reminding Test and the Logical Memory Task from Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels. - Brugulat-Serrat, Anna; Cañas, Alba; Canals, Lidia; Marne, Paula; Gramunt, Nina; Milà-Alomà, Marta; Suárez-Calvet, Marc; Arenaza-Urquijo, Eider M; Grau-Rivera, Oriol; González-de-Echávarri, José María; Minguillon, Carolina; Fauria, Karine; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment. OBJECTIVE: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers. METHODS: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable. RESULTS: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected. CONCLUSION: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.

Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment. - Guo, Mingyan; Peng, Jun; Huang, Xiaoyan; Xiao, Lingjun; Huang, Fenyan; Zuo, Zhiyi (J Alzheimers Dis, 2021)
BACKGROUND: Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare. OBJECTIVE: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI. METHODS: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected. RESULTS: Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI. CONCLUSION: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Asians; Biodiversity; China; Cognition; Cognitive Dysfunction; Disease Progression; Feces; Female; Gastrointestinal Microbiome; Humans; Male; Middle Aged; RNA, Ribosomal, 16S

Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer's Disease. - Cuervo-Zanatta, Daniel; Garcia-Mena, Jaime; Perez-Cruz, Claudia (J Alzheimers Dis, 2021)
BACKGROUND: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer's disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. OBJECTIVE: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. METHODS: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. RESULTS: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. CONCLUSION: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.
Keywords: Alzheimer Disease; Animals; Cognitive Dysfunction; Female; Gastrointestinal Microbiome; Humans; Male; Mice; Mice, Transgenic; Sex Characteristics; Spatial Memory

High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice. - Bao, Jian; Liang, Zheng; Gong, Xiaokang; Yu, Jing; Xiao, Yifan; Liu, Wei; Wang, Xiaochuan; Wang, Jian-Zhi; Shu, Xiji (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series. - Dhaynaut, Maeva; Sprugnoli, Giulia; Cappon, Davide; Macone, Joanna; Sanchez, Justin S; Normandin, Marc; Guehl, Nicolas; Koch, Giacomo; Paciorek, Rachel; Connor, Ann; Press, Daniel; Johnson, Keith; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Alzheimer's disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. OBJECTIVE: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). METHODS: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. RESULTS: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. CONCLUSION: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

Impact of Social Isolation on People with Dementia and Their Family Caregivers. - Azevedo, Lílian Viana Dos Santos; Calandri, Ismael Luis; Slachevsky, Andrea; Graviotto, Héctor Gastón; Vieira, Maria Carolina Santos; Andrade, Caíssa Bezerra de; Rossetti, Adriana Peredo; Generoso, Alana Barroso; Carmona, Karoline Carvalho; Pinto, Ludmilla Aparecida Cardoso; Sorbara, Marcos; Pinto, Alejandra; et al. (J Alzheimers Dis, 2021)
BACKGROUND: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms. OBJECTIVE: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers. METHODS: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers. RESULTS: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0%of people with dementia. In addition, 31.2%of individuals with dementia felt sadder and 37.4%had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia. CONCLUSION: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries.
Keywords: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Argentina; Brazil; Caregivers; Chile; COVID-19; Dementia; Female; Humans; Male; Middle Aged; Pandemics; Physical Distancing; Social Isolation; Surveys and Questionnaires

Improving the Diagnosis of the Frontal Variant of Alzheimer's Disease with the DAPHNE Scale. - Lehingue, Elsa; Gueniat, Julien; Jourdaa, Sandra; Hardouin, Jean BenoÎt; Pallardy, Amandine; Courtemanche, Hélène; Rocher, Laetitia; Etcharry-Bouyx, Frédérique; Auriacombe, Sophie; Mollion, Hélène; Formaglio, Maıté; Rouaud, Olivier; et al. (J Alzheimers Dis, 2021)
BACKGROUND: The frontal variant of Alzheimer's disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. OBJECTIVE: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. METHODS: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. RESULTS: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. CONCLUSION: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.
Keywords: Aged; Alzheimer Disease; Cohort Studies; Diagnosis, Differential; Female; Frontal Lobe; Frontotemporal Dementia; Humans; Male; Middle Aged; Neuropsychological Tests

Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging. - Wang, Xuewei; Bui, Hai; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jack, Clifford R; Petersen, Ronald C; Mielke, Michelle M (J Alzheimers Dis, 2021)
BACKGROUND: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. OBJECTIVE: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. RESULTS: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. CONCLUSION: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults. - Gardener, Samantha L; Weinborn, Michael; Sohrabi, Hamid R; Doecke, James D; Bourgeat, Pierrick; Rainey-Smith, Stephanie R; Shen, Kai-Kai; Fripp, Jurgen; Taddei, Kevin; Maruff, Paul; Salvado, Olivier; Savage, Greg; et al. (J Alzheimers Dis, 2021)
BACKGROUND: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. OBJECTIVE: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. METHODS: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30-44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. RESULTS: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. CONCLUSION: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

Longitudinally Increasing Elevated Asymmetric Flortaucipir Binding in a Cognitively Unimpaired Amyloid-Negative Older Individual. - Schwarz, Christopher G; Knopman, David S; Ramanan, Vijay K; Lowe, Val J; Wiste, Heather J; Cogswell, Petrice M; Utianski, Rene L; Senjem, Matthew L; Gunter, Jeffrey R; Vemuri, Prashanthi; Petersen, Ronald C; Jack, Clifford R (J Alzheimers Dis, 2021)
We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.

Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study. - Cuttler, Jerry M; Abdellah, Eslam; Goldberg, Yael; Al-Shamaa, Sarmad; Symons, Sean P; Black, Sandra E; Freedman, Morris (J Alzheimers Dis, 2021)
BACKGROUND: In 2015, a patient in hospice with Alzheimer's disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD. OBJECTIVE: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the same treatments are given. METHODS: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments. RESULTS: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change. CONCLUSION: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD.
Keywords: Aged, 80 and over; Alzheimer Disease; Cranial Irradiation; Female; Humans; Male; Pilot Projects; Radiation, Ionizing

Medical and Social Determinants of Brain Health and Dementia in a Multicultural Community Cohort of Older Adults. - Galvin, James E; Chrisphonte, Stephanie; Chang, Lun-Ching (J Alzheimers Dis, 2021)
BACKGROUND: Socioeconomic status (SES), race, ethnicity, and medical comorbidities may contribute to Alzheimer's disease and related disorders (ADRD) health disparities. OBJECTIVE: Analyze effects of social and medical determinants on cognition in 374 multicultural older adults participating in a community-based dementia screening program. METHODS: We used the Montreal Cognitive Assessment (MoCA) and AD8 as measures of cognition, and a 3-way race/ethnicity variable (White, African American, Hispanic) and SES (Hollingshead index) as predictors. Potential contributors to health disparities included: age, sex, education, total medical comorbidities, health self-ratings, and depression. We applied K-means cluster analyses to study medical and social dimension effects on cognitive outcomes. RESULTS: African Americans and Hispanics had lower SES status and cognitive performance compared with similarly aged Whites. We defined three clusters based on age and SES. Cluster #1 and #3 differed by SES but not age, while cluster #2 was younger with midlevel. Cluster #1 experienced the worse health outcomes while cluster #3 had the best health outcomes. Within each cluster, White participants had higher SES and better health outcomes, African Americans had the worst physical performance, and Hispanics had the most depressive symptoms. In cross-cluster comparisons, higher SES led to better health outcomes for all participants. CONCLUSION: SES may contribute to disparities in access to healthcare services, while race and ethnicity may contribute to disparities in the quality and extent of services received. Our study highlights the need to critically address potential interactions between race, ethnicity, and SES which may better explain disparities in ADRD health outcomes.

Mild Behavioral Impairment and Subjective Cognitive Decline Predict Cognitive and Functional Decline. - Ismail, Zahinoor; McGirr, Alexander; Gill, Sascha; Hu, Sophie; Forkert, Nils D; Smith, Eric E (J Alzheimers Dis, 2021)
BACKGROUND: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease). OBJECTIVE: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline. METHODS: Cognitively normal participants were followed up annually at Alzheimer's Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome. RESULTS: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD- (20.7%), and 8.15 [5.71-11.64] for MBI+SCD+(30.9%). CONCLUSION: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Disease Progression; Executive Function; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Odds Ratio; Risk Assessment

Mortality After Ischemic Stroke in Patients with Alzheimer's Disease Dementia and Other Dementia Disorders. - Zupanic, Eva; von Euler, Mia; Winblad, Bengt; Xu, Hong; Secnik, Juraj; Kramberger, Milica Gregoric; Religa, Dorota; Norrving, Bo; Garcia-Ptacek, Sara (J Alzheimers Dis, 2021)
BACKGROUND: Stroke and dementia are interrelated diseases and risk for both increases with age. Even though stroke incidence and age-standardized death rates have decreased due to prevention of stroke risk factors, increased utilization of reperfusion therapies, and other changes in healthcare, the absolute numbers are increasing due to population growth and aging. OBJECTIVE: To analyze predictors of death after stroke in patients with dementia and investigate possible time and treatment trends. METHODS: A national longitudinal cohort study 2007-2017 using Swedish national registries. We compared 12,629 ischemic stroke events in patients with dementia with matched 57,954 stroke events in non-dementia controls in different aspects of patient care and mortality. Relationship between dementia status and dementia type (Alzheimer's disease and mixed dementia, vascular dementia, other dementias) and death was analyzed using Cox regressions. RESULTS: Differences in receiving intravenous thrombolysis between patients with and without dementia disappeared after the year 2015 (administered to 11.1% dementia versus 12.3% non-dementia patients, p = 0.117). One year after stroke, nearly 50% dementia and 30% non-dementia patients had died. After adjustment for demographics, mobility, nursing home placement, and comorbidity index, dementia was an independent predictor of death compared with non-dementia patients (HR 1.26 [1.23-1.29]). CONCLUSION: Dementia before ischemic stroke is an independent predictor of death. Over time, early and delayed mortality in patients with dementia remained increased, regardless of dementia type. Patients with≤80 years with prior Alzheimer's disease or mixed dementia had higher mortality rates after stroke compared to patients with prior vascular dementia.
Keywords: Aged; Aged, 80 and over; Comorbidity; Dementia; Female; Fibrinolytic Agents; Humans; Incidence; Ischemic Stroke; Male; Registries; Survival Rate; Sweden; Thrombolytic Therapy

Near-Infrared Optical Spectroscopy In Vivo Distinguishes Subjects with Alzheimer's Disease from Age-Matched Controls. - Greco, Frank A; McKee, Ann C; Kowall, Neil W; Hanlon, Eugene B (J Alzheimers Dis, 2021)
BACKGROUND: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer's disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need. OBJECTIVE: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy. METHODS: NIR spectra were acquired in vivo. Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished "AD-alone" (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases. RESULTS: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2). CONCLUSION: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo. A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions.

Needs of Dementia Family Caregivers in Spain During the COVID-19 Pandemic. - Carcavilla, Nuria; Pozo, Ana Sofía; González, Belén; Moral-Cuesta, Débora; Roldán, José Joaquín; Erice, Victoria; Remírez, Ana de Ganuza (J Alzheimers Dis, 2021)
We explored the experience from caregivers of people with dementia (PwD) during mandatory confinement due to the COVID-19 pandemic in Spain. An online survey, which studied the perceptions of the main problems and consequences experienced during confinement, was answered by 106 family caregivers of PwD. Results showed that family caregivers of PwD experienced psychological problems, like anxiety, mood, sleep, or eating disorders during confinement and felt less supported when they had to handle challenging behaviors or offer meaningful activities. An innovative multi-tiered supportive approach is needed which considers a post-pandemic reality and ensures the continuity of quality care for PwD and their family careers.
Keywords: Adaptation, Psychological; Aged; Aged, 80 and over; Alzheimer Disease; Anxiety Disorders; Caregivers; COVID-19; Feeding and Eating Disorders; Female; Humans; Male; Middle Aged; Mood Disorders; Needs Assessment; Sleep Wake Disorders; Social Isolation; Social Support; Spain

New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer's Disease. - Guzmán-Martínez, Leonardo; Calfío, Camila; Farías, Gonzalo A; Vilches, Cristian; Prieto, Raul; Maccioni, Ricardo B (J Alzheimers Dis, 2021)
One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.
Keywords: Acupuncture Therapy; Aging; Alzheimer Disease; Biomarkers; Dietary Supplements; Early Diagnosis; Humans; Medicine, Chinese Traditional; Meditation; Quality of Life; Treatment Outcome