Abnormal epigenetic modification of lysosome and lipid regulating genes in Alzheimer's disease. - Ruan, Tingting; Ling, Yunxiang; Wu, Can; Niu, Yanfang; Liu, Guili; Xu, Chunshuang; Lv, Zhongyue; Yuan, Yalan; Zhou, Xinkai; Wang, Qinwen; Xu, Shujun (J Alzheimers Dis, 2025)
BackgroundAbnormal lipid metabolism has been identified as a potential pathogenic mechanism of Alzheimer's disease (AD), which might be epigenetically regulated. Lysosomes are critical organelles for lipid metabolism. However, the epigenetic modifications of lysosome and lipid regulating genes remain unclear in AD patients.ObjectiveExplore the role of abnormal epigenetic modifications, especially methylation of lysosome and lipid metabolism-related genes in AD.MethodsMethylation beadchip and MALDI-TOF mass spectrometry were used to detect genome-wide DNA methylation levels and validate key gene methylation, respectively. Clinical data were collected from all participants. Associations between clinical biochemical characteristics and altered DNA methylation in AD patients were analyzed, and a risk factor model of AD was established.Results41 differentially methylated positions (DMPs) corresponding to 33 genes were identified in AD patients, with 18 hypermethylated and 23 hypomethylated positions. Significant alterations were observed in lipid regulating genes () and lysosomal transmembrane gene (). Clinical analysis revealed that TP, ALB, IB, ADA, ALP, HCY, GLU, TC, BUN, HDL-C, LDL-C, and APOA1 levels were significantly higher in AD patients, whereas A/G and DB levels were lower. hypermethylation was further verified and found to correlate with TC, HDL-C, LDL-C, APOA1, IB, and HCY. The AUC of the AD risk model, which integrated clinical lipid markers and methylation, reached 0.9519 (< 0.0001).ConclusionsAbnormal epigenetic regulation of lysosomal gene and lipid dyshomeostasis were high-risk factors in AD. Methylation modifications of lysosome and lipid regulating genes might be key processes in AD pathogenesis.

Alzheimer's disease-related cortical proteins modify the association of brain insulin signaling with cognitive decline. - Tong, Han; Petyuk, Vladislav A; Sendtner, Michael; Sood, Ajay; Bennett, David A; Capuano, Ana W; Arvanitakis, Zoe (J Alzheimers Dis, 2025)
BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pTAKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cognitive Dysfunction; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 5; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

ApoE ε4-dependent Alteration of CXCR3 CD127 CD4 T cells associates with elevated plasma neurofilament light chain in Alzheimer's disease. - Hu, Dan; Chen, Mei; Li, Xuyang; Daley, Sarah; Morin, Peter; Han, Yuyang; Hemberg, Martin; Weiner, Howard L; Xia, Weiming (J Alzheimers Dis, 2025)
BackgroundRecent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer's disease (AD).ObjectiveTo characterize the composition of adaptive immune cells in the peripheral blood of AD patients.MethodsWe utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects.ResultsWe found that the abundance of proinflammatory CXCR3  CD127 Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3  CD127 Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3 CD127 Th1 cells in the CSF of AD patients was further increased compared to HCs.ConclusionsThese results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3  CD127 Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.

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.

Association of Alzheimer's disease biomarkers with low premorbid intellectual functioning in a multi-ethnic community-dwelling cohort: A cross-sectional study of HABS-HD. - Abdullah, Lubnaa; Zhou, Zhengyang; Hall, James; Petersen, Melissa; Zhang, Fan; O'Bryant, Sid (J Alzheimers Dis, 2025)
Individuals with intellectual disability (ID) may have a five-fold increased risk for developing Alzheimer's disease (AD). However, studies investigating brain aging among individuals with ID without Down syndrome (DS) are lacking. To begin addressing this gap, our study utilized word reading, a widely recognized indicator of an individual's premorbid intellectual ability (pIQ), to examine the effects of ID without DS on plasma AD biomarker outcomes. To investigate the relationship between premorbid intellectual ability (pIQ) and plasma AD biomarkers in individuals with ID without DS, while considering ethnic differences in these associations. Participants from the Health & Aging Brain Study - Health Disparities (HABS-HD) were categorized into low (z ≤ -2.00) or average (z = 0.00 ± 1.00) pIQ groups based on word reading scores. Plasma biomarkers including Aβ, Aβ, Aβ, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-tau) were assayed using Simoa technology. Individuals with low pIQ exhibited significantly higher levels of p-Tau181 ( < 0.05), NfL ( < 0.05), and t-tau ( < 0.05) compared to those with average pIQ. Stratified analysis by ethnicity revealed differential associations, with Hispanic and non-Hispanic White (NHW) participants showing distinct biomarker profiles relative to non-Hispanic Black (NHB) individuals. The findings demonstrate that low pIQ is a reliable factor associated with plasma AD biomarker outcomes. Ethnicity appears to modulate these associations, suggesting complex interactions between factors driving AD susceptibility across diverse populations. This study highlights the importance of considering both pIQ and ethnicity in neurodegenerative processes, particularly in individuals with non-DS intellectual developmental disability.

Associations of dietary protein and amino acid intakes with disability-adjusted life years for Alzheimer's disease in Japanese people. - Ishikawa-Takata, Kazuko; Fujiwara, Kazuki; Tanaka, Takayuki; Nakamura, Keiji; Kobayashi, Hisamine; Okada, Shinobu (J Alzheimers Dis, 2025)
BackgroundThe number of patients with dementia is increasing worldwide. In Japan, dementia is the most significant reason recognized for people requiring nursing care. Protein is one of the possible preventive nutrients for dementia; however, adequate intake levels can differ according to usual protein intakes and protein sources.ObjectiveThis study examined the relationships between disability-adjusted life years (DALYs) for Alzheimer's disease and protein or amino acid intakes.MethodsGlobal Burden of Disease Study data (DALYs for each sex and age group in each year) and de-identified individual records from the National Health and Nutrition Survey Japan (data from 46,831 subjects) from 2001 to 2019 were used. Multiple regression analyses were conducted to assess the relationships between DALYs and protein or amino acid intakes with lifestyle factors and sociodemographic index as confounding factors.ResultsHigher protein-to-energy ratios were correlated with lower DALYs in women in their 70 s (partial regression coefficient [Coeff.] = -349.488,  = 0.034), in men in their 60 s (Coeff. = -51.484), and in both sexes combined in their 60 s (Coeff. = -26.696,  = 0.015) even after adjusting for other possible nutrient intakes. Additionally, elevated isoleucine, lysine, tyrosine, histidine, arginine, alanine, asparagine, and glycine levels were correlated with lower DALYs in women in their 70 s (Coeff. = -2.752 to -0.141).ConclusionsAdequate protein and specific amino acid intakes may be associated with DALYs for Alzheimer's disease.

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.

Brain-penetrant histone deacetylase inhibitor RG2833 improves spatial memory in females of an Alzheimer's disease rat model. - Ndukwe, Kelechi; Serrano, Peter A; Rockwell, Patricia; Xie, Lei; Figueiredo-Pereira, Maria E (J Alzheimers Dis, 2025)
BACKGROUND: Nearly two-thirds of Alzheimer's disease (AD) patients are women. Therapeutics for women are critical to lowering their elevated risk of developing this major cause of adult dementia. Moreover, targeting epigenetic processes such as histone acetylation that regulate multiple cellular pathways is advantageous given the multifactorial nature of AD. Histone acetylation takes part in memory consolidation, and its disruption is linked to AD. OBJECTIVE: Determine whether the investigational drug RG2833 has repurposing potential for AD. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. METHODS: RG2833 effects were determined on cognition, transcriptome, and AD-like pathology in 11-month TgF344-AD female and male rats. Treatment started early in the course of pathology when therapeutic intervention is predicted to be most effective. RESULTS: RG2833-treatment of 11-month TgF344-AD rats: (1) Significantly improved hippocampal-dependent spatial memory in females but not males. (2) Upregulated expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation in females. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at p < 0.05, false discovery rate <0.05, and fold-change equal or > 1.5. (3) Failed to improve amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. CONCLUSIONS: Our study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients.

Chronic gingivitis increases the risk of early-onset Alzheimer's disease. - Mo, Dongcan; Li, Xiaoling; He, Jing; Lin, Xiaozuo; Wang, Pingkai; Zeng, Yinan; Wu, Xiaoju; Liu, LiuYu; Chi, Li; Luo, Man (J Alzheimers Dis, 2025)
BackgroundPeriodontal disease has two types of inflammatory states: gingivitis and periodontitis. While studies suggest a link between periodontal disease and Alzheimer's disease (AD), current evidence is insufficient to establish causality. This study employed Mendelian randomization (MR) and bioinformatics to investigate causal relationships between gingivitis, periodontitis, and AD types, while identifying diagnostic biomarkers through transcriptome-based bioinformatics approaches.ObjectiveThis study aims to explore the causal relationship between periodontal disease and AD using MR combined with bioinformatics analysis, investigate potential pathogenesis, and construct/validate diagnostic biomarkers.MethodsExposures and outcomes were selected from the Open whole-genome association study. Causal relationships were assessed using inverse variance-weighted (IVW), MR-Egger, and other supplementary methods. Transcriptome sequencing datasets were downloaded from Gene Expression Omnibus datasets. Key pathways and functions were identified through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Protein-protein interaction and LASSO regression were used to construct and evaluate the diagnostic signature for early-onset AD (EOAD). Gene Set Enrichment Analysis was applied to analyze gene set enrichment between high and low-risk groups.ResultsIVW showed a positive correlation (OR = 1.161, 95% CI = 1.011-1.332, p = 0.035), and MR-Egger validated this result (OR = 1.296, 95% CI = 1.020-1.645, p = 0.049). These findings suggest that chronic gingivitis may increase EOAD risk. Reverse analysis results were negative. Immune activation, angiogenesis, and blood-brain barrier damage link the two diseases. The Inter-alpha-trypsin inhibitor heavy chain H5 () gene and pathway emerged in MR and bioinformatics analyses. A gene signature composed of , , and shows potential for diagnosing EOAD.ConclusionsChronic gingivitis may be associated with an increased risk of EOAD.

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.

DNA methylation age acceleration is associated with incident cognitive impairment in the health and retirement study. - Blostein, Freida; Bakulski, Kelly M; Fu, Mingzhou; Wang, Herong; Zawistowski, Matthew; Ware, Erin B (J Alzheimers Dis, 2025)
BackgroundDNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the association between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity.ObjectiveOur study aimed to investigate associations between DNA methylation clocks and incident cognitive impairment using a larger and US nationally-representative sample from the Health and Retirement Study.MethodsWe measured DNA methylation age acceleration in 2016 by regressing the DNA methylation clocks, including GrimAge, against chronological age. Cognitive change over time was determined by Langa-Weir cognition status from 2016 to 2018. Multivariable logistic regression evaluated the association between DNA methylation age acceleration and cognitive change, adjusting for cell-type proportions, demographic, and health factors. We also applied inverse probability weighting to address potential selection bias from varying loss-to-follow-up rates.ResultsThe analytic sample (N = 2713) was 54% female, 8.4% Black/African American, 86% White, 7.5% Hispanic, and 68 years old at baseline. During the two years of follow-up, 12% experienced cognitive change and had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those maintaining normal cognition (mean = -0.8 years). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive change during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11).ConclusionsOur study offers insights into DNA methylation age acceleration associated with cognitive change over time, suggesting avenues for improved prevention, diagnosis, and treatment.

Down syndrome and Alzheimer's disease: Oxidative stress in the neurodegenerative process. - Cordeiro, Augusto Magno Tranquezi; Singulani, Monique Patricio; Talib, Leda Leme; Forlenza, Orestes Vicente (J Alzheimers Dis, 2025)
BACKGROUND: Individuals with Down syndrome (DS) generally show neuropathological features of Alzheimer disease (AD). The trisomy of chromosome 21 causes an imbalance of antioxidant systems, which can be linked to AD pathophysiology. OBJECTIVE: Verify the difference between the activity of antioxidant enzymes and products of the oxidation process in peripheral blood in non-trisomic (NT) and trisomic (DS) adults and elders and respective associations with cognitive impairment. METHODS: A total of 120 subjects were included in this study. Sociodemographic and clinical information were collected as per protocol for participants in DS and NT groups. The cognitive state of the DS participants was established according to the Brazilian version of the Cambridge Examination for Mental Disorders of Older People with Down's syndrome and Others with Intellectual Disabilities (CAMDEX-DS). The CAMDEX interview was used for this purpose for participants in the NT group. Plasma samples were collected to evaluate protein carbonyl content, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE). RESULTS: We found increased levels of SOD and CAT activity in the DS group. When the groups were stratified by cognitive decline, elevated levels of SOD and CAT activity were found both in DS groups with and without decline. The activity of GPx was similar between the groups, as well as MDA and HNE. CONCLUSION: The results suggest that alterations of the antioxidative processes can be implicated in the onset of neurodegeneration observed in individuals with DS.

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.

EEG biomarkers for Alzheimer's disease: A novel automated pipeline for detecting and monitoring disease progression. - Simmatis, Leif Er; Russo, Emma E; Steininger, Tayo; Riddell, Haleigh; Chen, Evelyn; Chiu, Queenny; Lin, Michelle; Oh, Donghun; Taheri, Porsha; Harmsen, Irene E; Samuel, Nardin (J Alzheimers Dis, 2025)
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder that profoundly alters brain function and organization. Currently, there is a lack of validated functional biomarkers to aid in diagnosing and classifying AD. Therefore, there is a pressing need for early, accurate, non-invasive, and accessible methods to detect and characterize disease progression. Electroencephalography (EEG) has emerged as a minimally invasive technique to quantify functional changes in neural activity associated with AD. However, challenges such as poor signal-to-noise ratio-particularly for resting-state (rsEEG) recordings-and issues with standardization have hindered its broader application.ObjectiveTo conduct a pilot analysis of our custom automated preprocessing and feature extraction pipeline to identify indicators of AD and correlates of disease progression.MethodsWe analyzed data from 36 individuals with AD and 29 healthy participants recorded using a standard 19-channel EEG and features were processed using our custom end-t-end pipeline. Various features encompassing amplitude, power, connectivity, complexity, and microstates were extracted. Unsupervised machine learning (uniform manifold approximation and projection) and supervised learning (random forest classifiers with nested cross-validation) were used to characterize the dataset and identify differences between AD and healthy groups.ResultsOur pipeline successfully detected several new and previously established EEG-based measures indicative of AD status and progression, demonstrating strong external validity.ConclusionsOur findings suggest that this automated approach provides a promising initial framework for implementing EEG biomarkers in the AD patient population, paving the way for improved diagnostic and monitoring strategies.

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.

Impact of obesity on neuropsychiatric symptoms in Alzheimer's disease: Insights from the ADNI cohort. - Wang, Shuoshi; Ni, Jingnian; Wei, Mingqing; Li, Ting; Shi, Jing; Tian, Jinzhou (J Alzheimers Dis, 2025)
BackgroundObesity is a major global health issue linked to increased risks of dementia, including Alzheimer's disease (AD). While the association between obesity and neuropsychiatric symptoms (NPS) in AD remains underexplored, identifying these links could aid in weight management in AD patients.ObjectiveThis study investigates the relationship between body mass index (BMI) and NPS in AD dementia patients, focusing on the potential mediating role of systemic inflammation.MethodsWe employed Generalized Additive Models (GAMs) to explore the relationship between BMI and NPS, as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q). Participants were classified into ideal, overweight, and obese groups based on WHO criteria. Longitudinal analyses assessed the trajectory of NPI-Q scores in different groups over a one-year follow-up.ResultsBMI significantly affects NPI-Q total scores and specific symptoms, including delusions, hallucinations, agitation/aggression, elation/euphoria, disinhibition, irritability/lability, aberrant motor behavior, nighttime disturbances, and appetite/eating disturbances. Obese patients exhibited higher NPI-Q total scores and greater severity in symptoms such as hallucinations, agitation/aggression, elation/euphoria, apathy/indifference, disinhibition, aberrant motor behavior, and nighttime disturbances. Additionally, CRP and complement C3 were identified as mediators in the relationship between obesity and NPS, highlighting the role of systemic inflammation.ConclusionsThis study demonstrates that obesity is associated with a heightened burden of NPS in AD dementia patients. The identification of CRP and complement C3 as mediators suggests inflammation plays a crucial role in the association between obesity and NPS. These findings underscore the importance of addressing obesity and its inflammatory consequences in managing NPS among this vulnerable population.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Cohort Studies; Female; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Obesity

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.

Increased unedited Alu RNA patterns found in cortex extracellular vesicles in Alzheimer's disease resemble hippocampus vasculature Alu RNA editing patterns but not cortex Alu RNA editing patterns. - Crooke, Philip S; Tossberg, John T; Aune, Thomas M (J Alzheimers Dis, 2025)
BACKGROUND: Endogenous Alu RNAs form double-stranded RNAs recognized by double-stranded RNA sensors and activate IRF and NF-kB transcriptional paths and innate immunity. Deamination of adenosines to inosines by the ADAR family of enzymes, a process termed A-to-I editing, disrupts double-stranded RNA structure and prevents innate immune activation. Innate immune activation is observed in Alzheimer's disease, the most common form of dementia. We have previously reported loss of A-to-I editing in hippocampus vasculature, but no change in cortex or cortex vasculature, associated with Alzheimer's disease. OBJECTIVE: Here, we investigated the status of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer's disease. METHODS: We used existing RNA-seq data sets and the SPRINT software package to determine levels of Alu RNA A-to-I editing in cortex extracellular vesicles in Alzheimer's disease and control groups and compared these editing profiles to those found in both total cortex and hippocampus vasculature. RESULTS: We find substantial loss of Alu A-to-I editing in cortex extracellular vesicles in Alzheimer's disease. By measuring editing patterns on a gene-by-gene basis, we determined that editing patterns in cortex extracellular vesicles resemble editing patterns in hippocampus vasculature rather than total cortex. CONCLUSIONS: We conclude that hippocampus vasculature unedited Alu RNAs are packaged in extracellular vesicles, travel to the cortex, deliver their cargo and stimulate innate immunity and alter other basic biological processes contributing to Alzheimer's disease progression.

Interactive effects of ɛ4 status and vascular burden on white matter microstructural integrity in aging with and without neurocognitive decline. - Konwar, Srijan; Manca, Riccardo; De Marco, Matteo; Soininen, Hilkka; Venneri, Annalena (J Alzheimers Dis, 2025)
BackgroundCarrying the Apolipoprotein () ε4 allele lowers age of onset and increases Alzheimer's disease (AD) risk. Neuropathological findings suggest a mixed etiology in many AD patients, and vascular pathology is common.ObjectiveThis study tested the interactive effect of status and multiple vascular comorbidities on white matter (WM) microstructure in aging and early AD.Methods195 participants from the VPH-DARE@IT dataset were stratified in low/high vascular burden based on the Framingham Risk Score (BMI version). Tract-based spatial statistics was used for WM analyses.ResultsThere was a main effect of , with ɛ4 carriers having higher fractional anisotropy (FA) and lower axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD) than non-carriers. There was a main effect of vascular burden with lower FA and higher AxD, MD, and RD in the high-burden than the low-burden group. A significant interaction between genotype and vascular burden was also found for all diffusion indices. comparisons revealed lower left hemisphere WM integrity when comparing the low risk group (i.e., non-carriers low burden) to intermediate risk groups (i.e., non-carriers high burden or ɛ4 carriers low burden). The contrasts between the two intermediate risk groups showed altered WM integrity bilaterally. Only the non-carriers high burden showed greater alterations in WM integrity when compared with the high risk group (i.e., ɛ4 carriers high burden) mainly in right hemisphere tracts.ConclusionsThese findings indicate an interactive effect of a risk gene and vascular comorbidities on WM integrity in aging and early AD.

Investigating the effects of 40 Hz sound stimulation on Alzheimer's disease pathways: Modulation of amyloid-β42 secretion, tau phosphorylation, phagocytosis, and autophagy. - Yang, Yuan-Han; Chang, Hsi-Wen; Chien, Ching-Fang; Hour, Tzyh-Chyuan (J Alzheimers Dis, 2025)
BackgroundAlzheimer's disease (AD) is the main cause of dementia in an aging society. Previous studies have demonstrated that non-invasive light flicker and sound with gamma frequency oscillations can modulate AD-related pathology in AD mice, potentially improving patient outcomes. However, the molecular mechanism by which sound with gamma frequency oscillations inhibits the expression of amyloid-β (Aβ) and the phosphorylation of tau, and modulating cell autophagy in nerve cells are still unclear.ObjectiveThis study aimed to explore the molecular effects of 40 Hz sound stimulation on AD-related pathways in a cellular model.MethodsWe designed a 40 Hz stimulating sound (H multi-frequency audio) for this study, and cells were exposed to H multi-frequency audio. The concentration of Aβ was quantified by enzyme-linked immunosorbent assay. Protein levels were examined by western blotting. Phagocytosis was examined by confocal microscopy and phagocytic analysis.ResultsFirst, we found that exposure to the 40 Hz stimulating sound inhibited the secretion of Aβ by activating the AβPP/ADAM10 pathway and suppressing the AβPP/BACE1 pathway. Second, 40 Hz stimulating sound inhibited tau phosphorylation at Thr181 through the inactivation of the Akt/mTOR pathway. Third, 40 Hz stimulating sound enhanced the phagocytosis and autophagy of Aβ through the AMPK/ULK/LC3B pathway in cells.ConclusionsOur study showed that 40 Hz stimulating sound is involved in the inhibition of Aβ secretion, p-Tau protein expression, and the promotion of phagocytosis and Aβ autophagy in cells. We suggest that 40 Hz stimulating sound could be a potential intervention to attenuate AD progression in the future.

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins. - Thorwald, Max A; Sta Maria, Naomi S; Chakhoyan, Ararat; O'Day, Peggy A; Jacobs, Russell E; Zlokovic, Berislav; Finch, Caleb E (J Alzheimers Dis, 2025)
BACKGROUND: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimer's disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO and other chelators do enter the brain despite some contrary reports. OBJECTIVE: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid-β protein precursor (AβPP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. METHODS: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and AβPP processing by western blot. RESULTS: DFO decreased brain iron 18% ( < 0.01) estimated by R2 MRI and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. AβPP and secretase enzymes also decreased by 30%. CONCLUSIONS: WT mice respond to DFO with decreased AβPP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered AβPP and secretase enzymes.

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.

Lifespan of male and female APP/PS1 and APP mouse models of Alzheimer's disease. - Roberts, Hannah; Fang, Yimin; Quinn, Kathleen; Hill, Tiarra; Peck, Mackenzie R; Bartke, Andrzej; Hascup, Kevin N; Hascup, Erin R (J Alzheimers Dis, 2025)
Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APP) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APP mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

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.

Neuropsychological phenotypic characteristics in a cohort of community-based older adults: Data from the Framingham Heart Study. - De Anda-Duran, Ileana; Hwang, Phillip H; Drabick, Deborah Ag; Andersen, Stacy L; Au, Rhoda; Libon, David J (J Alzheimers Dis, 2025)
BackgroundNeuropsychological (NP) assessment is crucial for diagnosing prodromal and Alzheimer's disease and related dementia (ADRD) syndromes. Yet, traditional NP scores often overlook errors and the process by which summary scores are obtained; information that can provide deeper insights into cognitive impairments and clinical heterogeneity.ObjectiveTo classify community-dwelling adults into neurocognitive phenotypes, identify NP test errors and processes that differentiate between groups, and explore their association with brain imaging measures.MethodsFramingham Heart Study (FHS) data were analyzed, focusing on NP summary scores and errors derived from the Boston Process Approach. Latent class analysis identified distinct neurocognitive phenotypes. Regression analyses assessed the relationships with NP errors and brain MRI measures.ResultsA total of 1195 participants (mean age 69.6 and 56.3% women) were included. Cognitively normal (CN), moderate-mixed, and dysexecutive impairment groups were identified. The number of Trail Making Test - Part B (TMT-B) pen lifts and TMT-B examiner-corrected errors were associated with the dysexecutive phenotype and differentiated it from the CN group (OR = 1.39, 95% CI = 1.28-1.52, p < 0.001, AUC = 0.85 and OR = 3.40, 95% CI = 2.65-4.38, p < 0.001, AUC = 0.92; respectively). Similarly, Boston Naming Test (BNT) circumlocution errors were associated with the moderate-mixed phenotype and differentiated it from the CN group (OR = 1.87, 95% CI = 1.49-2.35, p < 0.001, AUC = 0.81). These scores were significantly associated with reduced hippocampal volumes.ConclusionsDetailed NP error and process analysis enhances traditional methods, offering a comprehensive approach to identifying and understanding cognitive impairments.

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.

Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway. - Zhai, Yanyu; Lu, Kaili; Yuan, Yuan; Zhang, Ziyao; Xue, Lixia; Zhao, Fei; Xu, Xiaofeng; Wang, Hongmei (J Alzheimers Dis, 2025)
BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.

Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period. - Park, Chang Hyun; Lee, Hyunji; Lee, Young-Min; Lee, Byung-Dae; Moon, Eunsoo; Suh, Hwagyu; Kim, Kyungwon; Kim, Hak-Jin; Shim, Hwanwook; Pak, Kyoungjune; Choi, Kyung-Un; Kim, Chang-Seok (J Alzheimers Dis, 2025)
BACKGROUND: Hippocampal atrophy is implicated in the early onset of Alzheimer's disease (AD). It is closely associated with rapid cognitive decline and serves as a critical predictor for conversion from mild cognitive impairment (MCI) to AD. Consequently, with growing interest in utilizing hippocampal volume (HV) as an outcome measure in clinical trials, elucidating the neurobiological mechanisms underlying hippocampal atrophy is essential for early diagnosing AD and predicting its progression. OBJECTIVE: The risk of AD associated with the apolipoprotein E ε4 () allele is higher in females than in males. However, the presence of sex-specific effects of the genotype on longitudinal hippocampal atrophy (ΔHV) remains unclear. We aimed to examine the effects of the interaction between the genotype and sex on ΔHV in amnestic mild cognitive impairment (aMCI). METHODS: This hospital-based prospective longitudinal study included 73 patients with aMCI. ΔHV, the major outcome measure, was assessed using magnetic resonance imaging performed at a baseline date and 2 years after the baseline evaluation. A two-way analysis of variance was conducted to examine the effects of the interaction between the genotype and sex on ΔHV over the 2-year period. RESULTS: A significant interaction was observed between and sex concerning ΔHV (= 0.036). In females, ΔHV significantly correlated with the status. Female carriers (ε3/ε4) exhibited 2.3 times higher ΔHV compared with female non-carriers (ε3/ε3) (-0.51 ± 0.28 versus -0.22 ± 0.26, < 0.001). In contrast, ΔHV was not linked to the status in males (= 0.599). CONCLUSIONS: We identified that the genotype affected ΔHV in females. Our findings suggest that female carriers, unlike males, may be more susceptible than non-carriers to the underlying pathophysiological mechanisms of hippocampal atrophy in aMCI.

Social isolation, loneliness, genetic risk, and incident dementia in people with type 2 diabetes mellitus: A population-based cohort study. - He, Zhixuan; Nie, Yu; Zhang, Weijie; Liu, Yue; Liu, Yaping; Xue, Huachen; Ai, Sizhi; Feng, Hongliang; Zhou, Yujing; Zhang, Jihui; Liang, Yan Yannis; Ning, Yuping (J Alzheimers Dis, 2025)
BackgroundSocial isolation and loneliness, two independent constructs of social disengagement, are becoming increasingly recognized factors for dementia risk.ObjectiveWe aimed to investigate whether these two constructs also associate with dementia risk in individuals with type 2 diabetes mellitus (T2DM), which is becoming more prevalent.MethodsThe longitudinal study included 24,986 participants (mean age: 60.0 ± 6.9 years, median follow-up: 12.0 years) with T2DM at baseline from the UK Biobank. Social isolation and loneliness were assessed using self-reported questionnaires. Genetic risk factors for dementia including polygenic risk score (PRS) and genotype were extracted. We identified incident dementia cases by linking hospital records and death registries.ResultsSocial isolation (most versus least: hazard ratio, HR: 1.46 [95% confidence intervals, CI: 1.22-1.75]) and loneliness (yes versus no: 1.56 [1.25-1.95]) were associated with an increased risk of incident dementia after adjusting for demographic factors; however, such associations attenuated when further adjusting for health behaviors, psychological factors, or diabetes-related characteristics. The social isolation-dementia association was predominantly attributable to health behaviors (48% for the most social isolation), while the loneliness-dementia association was largely explained by psychological factors (46%). Significant modification effects of dementia genetic risk were observed in these associations.ConclusionsSocial isolation and loneliness were associated with a greater risk for incident dementia among T2DM individuals, with differential explanatory factors. The genetic risk for dementia modified these associations. The findings underscore the importance of strengthening social connections to mitigate diabetes-related dementia risk.

White matter lesions rather than amyloid-β burden are associated with cognitive decline in Alzheimer's disease. - Kasahara, Hiroo; Ikeda, Masaki; Makioka, Kouki; Nakamura, Takumi; Takahashi, Ryoma; Kawarabayashi, Takeshi; Sanada, Etsuko; Suto, Takayuki; Higuchi, Tetsuya; Tsushima, Yoshito; Ikeda, Yoshio (J Alzheimers Dis, 2025)
We assessed the severity of amyloid-β accumulation and white matter lesions (WML) in the brain, and their association with cognitive decline, in patients (n = 47) with Alzheimer's disease (AD). The mean cortical standardized uptake value ratio (mcSUVR) was derived from amyloid positron emission tomography, while the percentage of WML area relative to brain parenchymal area was determined using magnetic resonance imaging. Cognitive decline was positively correlated with WML severity (= 0.50, = 0.042) but not mcSUVR (Aβ accumulation). Managing vascular risk factors can prevent cognitive decline in patients with AD.

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes. - Rolandsson, Olov; Tornevi, Andreas; Steneberg, Pär; Edlund, Helena; Olsson, Tommy; Andreasson, Ulf; Zetterberg, Henrik; Blennow, Kaj (J Alzheimers Dis, 2024)
BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. OBJECTIVE: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. METHODS: Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. RESULTS: At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. CONCLUSIONS: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.
Keywords: Aged; Amyloid beta-Peptides; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Insulysin; Male; Peptide Fragments

Addressing the Discrepancies Between Animal Models and Human Alzheimer's Disease Pathology: Implications for Translational Research. - Polis, Baruh; Samson, Abraham O (J Alzheimers Dis, 2024)
Animal models, particularly transgenic mice, are extensively used in Alzheimer's disease (AD) research to emulate key disease hallmarks, such as amyloid plaques and neurofibrillary tangles formation. Although these models have contributed to our understanding of AD pathogenesis and can be helpful in testing potential therapeutic interventions, their reliability is dubious. While preclinical studies have shown promise, clinical trials often yield disappointing results, highlighting a notable gap and disparity between animal models and human AD pathology. Existing models frequently overlook early-stage human pathologies and other key AD characteristics, thereby limiting their application in identifying optimal therapeutic interventions. Enhancing model reliability necessitates rigorous study design, comprehensive behavioral evaluations, and biomarker utilization. Overall, a nuanced understanding of each model's neuropathology, its fidelity to human AD, and its limitations is essential for accurate interpretation and successful translation of findings. This article analyzes the discrepancies between animal models and human AD pathology that complicate the translation of findings from preclinical studies to clinical applications. We also delve into AD pathogenesis and attributes to propose a new perspective on this pathology and deliberate over the primary limitations of key experimental models. Additionally, we discuss several fundamental problems that may explain the translational failures and suggest some possible directions for more effective preclinical studies.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Neurofibrillary Tangles; Reproducibility of Results; Translational Research, Biomedical

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

Agent Orange Herbicidal Toxin-Initiation of Alzheimer-Type Neurodegeneration. - de la Monte, Suzanne M; Tong, Ming (J Alzheimers Dis, 2024)
BACKGROUND: Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1 : 1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer's disease (AD). OBJECTIVE: This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. METHODS: Long Evans rat frontal lobe slice cultures treated with 250μg/ml of 2,4-D, 2,4,5-T, or both (D + T) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. RESULTS: Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AβPP, Aβ, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the D + T compared with 2,4-D or 2,4,5-T treated cultures. CONCLUSIONS: Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans.
Keywords: 2,4,5-Trichlorophenoxyacetic Acid; Agent Orange; Alzheimer Disease; Animals; Herbicides; Rats; Rats, Long-Evans

Aging-Related Protein Alterations in the Brain. - Syed, Rafay Ali; Hayat, Mahnoor; Qaiser, Hammad; Uzair, Mohammad; Al-Regaiey, Khalid; Khallaf, Roaa; Kaleem, Imdad; Bashir, Shahid (J Alzheimers Dis, 2024)
Aging is an intrinsic aspect of an organism's life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD.
Keywords: Aging; Alzheimer Disease; Animals; Brain; Humans; tau Proteins

Alpha-, Beta-, and Gamma-Secretase, Amyloid Precursor Protein, and Tau Protein Genes in the Hippocampal CA3 Subfield in an Ischemic Model of Alzheimer's Disease with Survival up to 2 Years. - Czuczwar, Stanisław J; Kocki, Janusz; Miziak, Barbara; Bogucki, Jacek; Bogucka-Kocka, Anna; Pluta, Ryszard (J Alzheimers Dis, 2024)
BACKGROUND: Understanding the phenomena underlying the non-selective susceptibility to ischemia of pyramidal neurons in the CA3 is important from the point of view of elucidating the mechanisms of memory loss and the development of dementia. OBJECTIVE: The aim of the study was to investigate changes in genes expression of amyloid precursor protein, its cleaving enzymes and tau protein in CA3 post-ischemia with survival of 12-24 months. METHODS: We used an ischemic model of Alzheimer's disease to study the above genes using an RT-PCR protocol. RESULTS: The expression of the amyloid precursor protein gene was above the control values at all times post-ischemia. The expression of the α-secretase gene also exceeded the control values post-ischemia. The expression of the β-secretase gene increased 12 and 24 months post-ischemia, and 18 months was below control values. Presenilin 1 and 2 genes expression was significantly elevated at all times post-ischemia. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months post-ischemia. CONCLUSIONS: The study suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid precursor protein. Additionally data indicate that brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a modified tau protein-dependent manner. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area post-ischemia. In addition expression of tau protein gene modification after brain ischemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Brain Ischemia; Hippocampus; Humans; Ischemia; tau Proteins

Alterations in Synaptic Connectivity and Synaptic Transmission in Alzheimer's Disease with High Physical Activity. - Wu, Can; Ruan, Tingting; Yuan, Yalan; Xu, Chunshuang; Du, Lijuan; Wang, Fang; Xu, Shujun (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegeneration disease. Physical activity is one of the most promising modifiable lifestyles that can be effective in slowing down the progression of AD at an early stage. OBJECTIVE: Explore the molecular processes impaired in AD that were conversely preserved and enhanced by physical activity. METHODS: Integrated transcriptomic analyses were performed in datasets that contain AD patients and elders with different degrees of physical activity. The changes of the hub genes were validated through analyzing another two datasets. The expression of the hub genes was further detected in the hippocampus and cortexes of APP/PS1 transgenic mice with or without physical activity by Quantitative polymerase chain reaction (qPCR). RESULTS: Cross-comparison highlighted 195 DEGs displaying opposed regulation patterns between AD and high physical activity (HPA). The common DEGs were predominantly involved in synaptic vesicle recycling and synaptic transmission, largely downregulated in AD patients but upregulated in the elders with HPA. Two key modules and four hub genes that were related to synaptic vesicle turnover were obtained from the PPI network. The expression of these hub genes (SYT1, SYT4, SH3GL2, and AP2M1) was significantly decreased in AD transgenic mice and was reversed by HPA training. CONCLUSIONS: HPA may reverse AD pathology by upregulating a range of synaptic vesicle transport related proteins which might improve the efficiency of synaptic vesicle turnover and facilitate inter-neuronal information transfer. The study provides novel insights into the mechanisms underlining the protective effects of HPA on AD.

Altered Neuronal Activity Patterns of the Prefrontal Cortex in Alzheimer's Disease After Transcranial Alternating Current Stimulation: A Resting-State fMRI Study. - Wang, Tao; Yan, Shaozhen; Shan, Yi; Xing, Yi; Bi, Sheng; Chen, Zhigeng; Xi, Hanyu; Xue, Hanxiao; Qi, Zhigang; Tang, Yi; Lu, Jie (J Alzheimers Dis, 2024)
BACKGROUND: Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer's disease (AD). However, the effects of tACS on brain activity remain unclear. OBJECTIVE: The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate the regional brain activity. RESULTS: Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. CONCLUSIONS: The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients.

Alzheimer DataLENS: An Open Data Analytics Portal for Alzheimer's Disease Research. - Noori, Ayush; Jayakumar, Rojashree; Moturi, Vaishnavi; Li, Zhaozhi; Liu, Rongxin; Serrano-Pozo, Alberto; Hyman, Bradley T; Das, Sudeshna (J Alzheimers Dis, 2024)
BACKGROUND: Recent Alzheimer's disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. OBJECTIVE: Create an online portal of public omics datasets for AD research. METHODS: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics pipeline. RESULTS: Alzheimer DataLENS currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. CONCLUSIONS: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org.
Keywords: Alzheimer Disease; Brain; Computational Biology; Genome-Wide Association Study; Humans; Internet

Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis. - Trieu, Calvin; Van Harten, Argonde C; Leeuwis, Anna E; Exalto, Lieza G; Hooghiemstra, Astrid M; Verberk, Inge M W; Allaart, Cor P; Brunner-La Rocca, Hans-Peter; Kappelle, L Jaap; van Oostenbrugge, Robert J; Biessels, Geert-Jan; Teunissen, Charlotte E; et al. (J Alzheimers Dis, 2024)
BACKGROUND: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. OBJECTIVE: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. METHODS: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. RESULTS: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. CONCLUSIONS: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Alzheimer's Disease Immunotherapy: Current Strategies and Future Prospects. - Aljassabi, Ali; Zieneldien, Tarek; Kim, Janice; Regmi, Deepika; Cao, Chuanhai (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Humans; Immunization, Passive; Immunotherapy; Inflammation

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

Amyloid-Directed Antibodies: Past, Present, and Future. - Noorda, Keith; Noorda, Kevin; Sabbagh, Marwan N; Bertelson, John; Singer, Jonathan; Decourt, Boris (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as "probable AD", and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. OBJECTIVE: This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD. METHODS: Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. RESULTS: This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. CONCLUSIONS: We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Immunotherapy

Amyloid-β Pathology Is the Common Nominator Proteinopathy of the Primate Brain Aging. - Ferrer, Isidro (J Alzheimers Dis, 2024)
Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging.
Keywords: Aging; Amyloid beta-Peptides; Animals; Brain; Humans; Neurofibrillary Tangles; Plaque, Amyloid; Primates; tau Proteins

Aniracetam: An Evidence-Based Model for Preventing the Accumulation of Amyloid-β Plaques in Alzheimer's Disease. - Love, Robert W B (J Alzheimers Dis, 2024)
Alzheimer's disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer's disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer's treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α-secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Neurofibrillary Tangles; Plaque, Amyloid; Pyrrolidinones; tau Proteins

Apoptosis, Autophagy, and Mitophagy Genes in the CA3 Area in an Ischemic Model of Alzheimer's Disease with 2-Year Survival. - Pluta, Ryszard; Bogucka-Kocka, Anna; Bogucki, Jacek; Kocki, Janusz; Czuczwar, Stanisław J (J Alzheimers Dis, 2024)
BACKGROUND: Currently, no evidence exists on the expression of apoptosis (CASP3), autophagy (BECN1), and mitophagy (BNIP3) genes in the CA3 area after ischemia with long-term survival. OBJECTIVE: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6-24 months. METHODS: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer's disease. RESULTS: First time, we demonstrated overexpression of the CASP3 gene in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. CONCLUSIONS: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3. This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia.
Keywords: Alzheimer Disease; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Brain Ischemia; CA3 Region, Hippocampal; Caspase 3; Disease Models, Animal; Male; Membrane Proteins; Mitochondrial Proteins; Mitophagy; Rats; Rats, Wistar

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems. - Loeffler, David A (J Alzheimers Dis, 2024)
Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Brain; Humans

The Association Between Distinct Delusional Ideations and Depressive Symptoms in Alzheimer's Disease: A Re-Analysis of CATIE-AD. - Nagata, Tomoyuki; Nakajima, Shinichiro; Kito, Shinsuke; Shinagawa, Shunichiro (J Alzheimers Dis, 2024)
BACKGROUND: Delusional ideations, one of neuropsychiatric symptoms (NPSs), are frequently shown in the long-term progression of Alzheimer's disease (AD), and comorbid with other NPSs including depression or agitation. Despite various types of delusional ideations, the comorbidity between each delusional ideation and depressive symptoms has not been discussed. OBJECTIVE: The present cross-sectional study is aimed at testing the hypothetical mechanism of comorbid pattern in AD. METHODS: Among 421 patients with AD, we analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease to compare age, sex, racial type, Mini-Mental State Examination (MMSE) scores, and Neuropsychiatric Inventory (NPI) depression score of between the presence and absence of each delusional ideation (delusion of persecution, theft, jealousy, abandonment, phantom boarder, Capgras syndrome, misidentification of place, or television sign). Next, with the stratification based on MMSE score of < or > = 15 points, we further explored association between delusional ideation and depressive symptom that was found significances in the primary analysis. RESULTS: Among eight subtypes of delusional ideations, depression score was higher in those with persecution delusion or Capgras syndrome. Moreover, the Capgras syndrome was associated with presence of depression in severer global cognitive impairment status. CONCLUSIONS: As comorbid NPSs of delusional ideation in AD, depressive severity is associated with specific delusional subtype: persecution delusion and Capgras syndrome. Capgras syndrome may be attributable to severe cognitive impairment in addition to depressive symptom. The consideration of pathogenetic differences in the distinct delusional ideations may be helpful for clinicians to select the treatment strategy.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cross-Sectional Studies; Delusions; Depression; Female; Humans; Male; Mental Status and Dementia Tests

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 Between Urinary Glyphosate Exposure and Cognitive Impairment in Older Adults from NHANES 2013-2014. - Ren, Jiawen; Yu, Yongquan; Wang, Yucheng; Dong, Yu; Shen, Xiaobing (J Alzheimers Dis, 2024)
BACKGROUND: Glyphosate is the most commonly used herbicide with potential neurotoxicity. However, limited epidemical evidence is found in the relationship between glyphosate and cognitive impairment, especially in the cognitive-disrupting sensitive elderly populations. OBJECTIVE: This study aimed to examine the association of urinary glyphosate exposure with cognitive impairment in the United State (US) older adults. METHODS: Cognitive impairment was determined by the following four tests: the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Immediate Recall test (IR), the CERAD Delayed Recall tests (DR), the Animal Fluency (AF) test and the Digit Substitution test (DSST). Survey weighted logistic regression and restricted cubic splines were applied to evaluate and visualize the association between glyphosate and cognitive impairment. RESULTS: A total of 465 elderly adults were identified in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle, and among them, 83.87% individuals had detectable urinary levels of glyphosate (0.628 ng/mL in average). After adjusting for the potential covariates, glyphosate was significantly linked to increased DR and AF impairment, and the corresponding ORs were 1.52 (1.01 to 2.30, p = 0.049) and 1.69 (1.11 to 2.59, p = 0.019), respectively. No significant association was identified between glyphosate and IR or DSST impairment. The RCS plot further confirmed the linear and positive relationships between glyphosate and DR and AF impairment. CONCLUSIONS: These findings suggested that exposure to glyphosate might be associated with declined cognitive function in the elderly, and it might be prudent to evaluate cognitive outcomes for aged individuals with glyphosate exposures.
Keywords: Aged; Alzheimer Disease; Cognition; Cognition Disorders; Cognitive Dysfunction; Glyphosate; Humans; Nutrition Surveys

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 Plastic Exposure with Cognitive Function Among Chinese Older Adults. - Zhu, Yongbin; Wu, Yueping; Shi, Liping; Yang, Yue; Wang, Yanrong; Pan, Degong; He, Shulan; Wang, Liqun; Li, Jiangping (J Alzheimers Dis, 2024)
BACKGROUND: The widespread exposure to plastic products and the increasing number of individuals with cognitive impairments have imposed a heavy burden on society. OBJECTIVE: This study aims to investigate the relationship between plastic product exposure in daily life and cognitive function in older Chinese individuals. METHODS: Data were obtained from the 2023 Ningxia Older Psychological Health Cohort, comprising 4045 participants aged 60 and above. Cognitive function was assessed using the Mini-Mental State Examination scale. A population-based plastic exposure questionnaire was used to calculate plastic exposure scores (PES). Binary logistic regression was employed to analyze the relationship between PES and cognitive function, while restricted cubic splines were used to examine the dose-response relationship between PES and cognitive function. Latent profile analysis (LPA) was employed to explore the potential patterns of plastic exposure, and logistic regression was used to investigate the relationship between different exposure patterns and cognitive function. A linear regression model was utilized to investigate the relationship between PES and different dimensions of cognitive function. RESULTS: Among the 4045 participants, 1915 individuals were assessed with mild cognitive impairment (MCI). After adjusting for all covariates, PES (OR = 1.04, 95% CI 1.02-1.06) was significantly associated with the risk of MCI and exhibited a dose-response relationship. LPA identified two potential categories of plastic exposure, with a higher risk of MCI observed in the group using plastic utensils. CONCLUSIONS: This study indicates a positive correlation between plastic exposure levels and MCI risk, particularly among individuals who frequently use plastic tableware.
Keywords: Aged; Aged, 80 and over; China; Cognition; Cognitive Dysfunction; Cohort Studies; East Asian People; Environmental Exposure; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Plastics; Surveys and Questionnaires

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

Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies. - Zhang, Xiao-Xue; Wang, He-Ran; Hu, Ya-Zhuo; Sun, Hong-Mei; Feng, Yu-Xin; Jia, Jian-Jun (J Alzheimers Dis, 2024)
BACKGROUND: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. OBJECTIVE: We summarized the current evidence from several aspects and further quantified these associations. METHODS: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. RESULTS: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. CONCLUSIONS: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Dementia; Humans; Prospective Studies; Risk Factors; Vitamin D; Vitamin D Deficiency

Associations Between Music and Dance Relationships, Rhythmic Proficiency, and Spatiotemporal Movement Modulation Ability in Adults with and without Mild Cognitive Impairment. - Slusarenko, Alexandra; Rosenberg, Michael C; Kazanski, Meghan E; McKay, J Lucas; Emmery, Laura; Kesar, Trisha M; Hackney, Madeleine E (J Alzheimers Dis, 2024)
BACKGROUND: Personalized dance-based movement therapies may improve cognitive and motor function in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer's disease. While age- and MCI-related deficits reduce individuals' abilities to perform dance-like rhythmic movement sequences (RMS)-spatial and temporal modifications to movement-it remains unclear how individuals' relationships to dance and music affect their ability to perform RMS. OBJECTIVE: Characterize associations between RMS performance and music or dance relationships, as well as the ability to perceive rhythm and meter (rhythmic proficiency) in adults with and without MCI. METHODS: We used wearable inertial sensors to evaluate the ability of 12 young adults (YA; age = 23.9±4.2 years; 9F), 26 older adults without MCI (OA; age = 68.1±8.5 years; 16F), and 18 adults with MCI (MCI; age = 70.8±6.2 years; 10F) to accurately perform spatial, temporal, and spatiotemporal RMS. To quantify self-reported music and dance relationships and rhythmic proficiency, we developed Music (MRQ) and Dance Relationship Questionnaires (DRQ), and a rhythm assessment (RA), respectively. We correlated MRQ, DRQ, and RA scores against RMS performance for each group separately. RESULTS: The OA and YA groups exhibited better MRQ and RA scores than the MCI group (p < 0.006). Better MRQ and RA scores were associated with better temporal RMS performance for only the YA and OA groups (r2 = 0.18-0.41; p < 0.045). DRQ scores were not associated with RMS performance in any group. CONCLUSIONS: Cognitive deficits in adults with MCI likely limit the extent to which music relationships or rhythmic proficiency improve the ability to perform temporal aspects of movements performed during dance-based therapies.

The Associations of Phosphorylated Tau 181 and Tau 231 Levels in Plasma and Cerebrospinal Fluid with Cognitive Function in Alzheimer's Disease: A Systematic Review and Meta-Analysis. - Li, Zhirui; Fan, Zixuan; Zhang, Qian (J Alzheimers Dis, 2024)
BACKGROUND: Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer's disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. OBJECTIVE: Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. METHODS: We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies-1,033 AD, 2,077 MCI, and 1,907 NC-were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% CIs. Begg tested publication bias. RESULTS: MCI patients had lower CSF p-tau181 levels than AD patients (SMD =-0.60, 95% CI (-0.85, -0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =-0.73, 95% CI (-1.04, -0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =-0.90, 95% CI (-0.82, -0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. CONCLUSIONS: CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition; Cognitive Dysfunction; Humans; tau Proteins

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.

BACE1 Inhibitors for Alzheimer's Disease: Current Challenges and Future Perspectives. - Coimbra, Judite R M; Resende, Rosa; Custódio, José B A; Salvador, Jorge A R; Santos, Armanda E (J Alzheimers Dis, 2024)
Disease-modifying therapies (DMT) for Alzheimer's disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Enzyme Inhibitors; Humans

Bisecting N-Acetylglucosamine Correlates with Phospho-Tau181 in Subjective Cognitive Decline but not in Control Cases. - Egebäck Arulf, Sofia; Ziyue Zhou, Robin; Kirsebom, Bjørn-Eivind; Jejcic, Alenka; Fladby, Tormod; Winblad, Bengt; Tjernberg, Lars; Schedin-Weiss, Sophia (J Alzheimers Dis, 2024)
BACKGROUND: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer's disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. OBJECTIVE: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified by amyloid/tau status and gender. METHODS: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. RESULTS: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. CONCLUSIONS: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline.

Blood Pressure Variability and Plasma Alzheimer's Disease Biomarkers in the SPRINT Trial. - Sible, Isabel J; Nation, Daniel A (J Alzheimers Dis, 2024)
BACKGROUND: Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer's disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels. OBJECTIVE: Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment. METHODS: In this post hoc analysis of the SPRINT trial, 457 participants (n = 206 in standard group, n = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0-4.0) years later to determine plasma AD biomarkers total tau and Aβ1-42:Aβ1-40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV×time on AD biomarker levels. RESULTS: Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: -0.02 [-0.19, 0.16], p = 0.843). BPV was not associated with Aβ 1-42:Aβ 1-40 ratio in either group. Mean BP was not associated with biomarkers. CONCLUSIONS: Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Blood Pressure; Humans; tau Proteins

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

Causal Association Between Sepsis and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization Study. - Zeng, Youjie; Cao, Si; Pang, Ke; Tang, Juan; Lin, Guoxin (J Alzheimers Dis, 2024)
BACKGROUND: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear. OBJECTIVE: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability. RESULTS: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer's disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy. CONCLUSIONS: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.
Keywords: Alzheimer Disease; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Neurodegenerative Diseases; Reproducibility of Results; Sepsis

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.

Cerebrovascular miRNAs Track Early Development of Alzheimer's Disease and Target Molecular Markers of Angiogenesis and Blood Flow Regulation. - Chum, Phoebe P; Bishara, Mary A; Solis, Summer R; Behringer, Erik J (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is associated with impaired cerebral circulation which underscores diminished delivery of blood oxygen and nutrients to and throughout the brain. In the 3xTg-AD mouse model, we have recently found that > 10 cerebrovascular miRNAs pertaining to vascular permeability, angiogenesis, and inflammation (e.g., let-7d, miR-99a, miR-132, miR-133a, miR-151-5p, and miR-181a) track early development of AD. Further, endothelial-specific miRNAs (miR-126-3p, miR-23a/b, miR-27a) alter with onset of overall AD pathology relative to stability of smooth muscle/pericyte-specific miRNAs (miR-143, miR-145). OBJECTIVE: We tested the hypothesis that cerebrovascular miRNAs indicating AD pathology share mRNA targets that regulate key endothelial cell functions such as angiogenesis, vascular permeability, and blood flow regulation. METHODS: As detected by NanoString nCounter miRNA Expression panel for 3xTg-AD mice, 61 cerebrovascular miRNAs and respective mRNA targets were examined using Ingenuity Pathway Analysis for canonical Cardiovascular (Cardio) and Nervous System (Neuro) Signaling. RESULTS: The number of targets regulated per miRNA were 21±2 and 33±3 for the Cardio and Neuro pathways respectively, whereby 14±2 targets overlap among pathways. Endothelial miRNAs primarily target members of the PDE, PDGF, SMAD, and VEGF families. Individual candidates regulated by≥4 miRNAs that best mark AD pathology presence in 3xTg-AD mice include CFL2, GRIN2B, PDGFB, SLC6A1, SMAD3, SYT3, and TNFRSF11B. CONCLUSION: miRNAs selective for regulation of endothelial function and respective downstream mRNA targets support a molecular basis for dysregulated cerebral blood flow regulation coupled with enhanced cell growth, proliferation, and inflammation.
Keywords: Alzheimer Disease; Angiogenesis; Animals; Biomarkers; Brain; Cerebrovascular Circulation; Disease Models, Animal; Endothelial Cells; Humans; Mice; Mice, Transgenic; MicroRNAs; Neovascularization, Pathologic

Characterizing Gut Microbiota in Older Chinese Adults with Cognitive Impairment: A Cross-Sectional Study. - Wang, Jing; Zhang, Gong; Lai, Hao; Li, Zengbin; Shen, Mingwang; Li, Chao; Kwan, Patrick; O'Brien, Terence J; Wu, Ting; Yang, Siyu; Zhang, Xueli; Zhang, Lei (J Alzheimers Dis, 2024)
BACKGROUND: Cognitive impairment is a clinical manifestation that occurs in the course of dementia like Alzheimer's disease. The association between cognitive impairment and gut microbiota is unclear. OBJECTIVE: We aimed to identify gut microbiota characteristics and key gut microbiota biomarkers associated with cognitive impairment in a relatively large cohort of older adults in China. METHODS: A total of 229 adults aged ≥60 years from Shenzhen, China were recruited into this cross-sectional study. Participants were divided into cognitive impairment (CI) and no cognitive impairment (NCI) groups according to the results of the Mini-Mental State Examination. Diversity analysis and network analysis were used to characterize the gut microbiota between the two groups. The linear discriminant analysis effect size method and machine learning approaches were sequentially performed to identify gut microbiota biomarkers. The relationship between biomarkers and lifestyle factors was explored using Transformation-based redundancy analysis (tb-RDA). RESULTS: A total of 74 CI participants and 131 NCI participants were included in the analysis. The CI group demonstrated lower α-diversity compared to the NCI group (Shannon: 2.798 versus 3.152, p < 0.001). The density of the gut microbiota interaction network was lower in the CI group (0.074) compared to the NCI group (0.081). Megamonas, Blautia, Pseudomonas, Stenotrophomonas, and Veillonella were key biomarkers for CI. The tb-RDA revealed that increased fruit intake and exercise contribute to a higher abundance of Megamonas, Blautia, and Veillonella. CONCLUSIONS: We identified a significantly reduced abundance of certain beneficial gut microbiota in older Chinese adults with cognitive impairment.
Keywords: Aged; Aged, 80 and over; Biomarkers; China; Cognitive Dysfunction; Cross-Sectional Studies; East Asian People; Female; Gastrointestinal Microbiome; Humans; Machine Learning; Male; Middle Aged

Circulating adipokines and MRI markers of brain aging in middle-aged adults from the community. - Satizabal, Claudia L; Himali, Jayandra Jung; Conner, Sarah C; Beiser, Alexa S; Maillard, Pauline; Vasan, Ramachandran S; DeCarli, Charles; Seshadri, Sudha (J Alzheimers Dis, 2024)
BACKGROUND: Midlife obesity is related to late-onset dementia. Studying adipose tissue-secreted adipokines in the context of brain aging may help us understand this association. OBJECTIVE: To investigate associations between adipokines and brain MRI markers in middle-aged adults from the Third-Generation cohort of the Framingham Heart Study. METHODS: Serum adiponectin, retinol-binding protein 4 (RBP4), fetuin-A, and Fatty Acid-Binding Protein 4 (FABP4) concentrations were measured by enzymatic immunoassays. MRI measures included total brain, cortical gray matter, hippocampal (total and anterior), lateral ventricular, and white matter hyperintensity volumes. We used linear regression models to separately relate adipokine concentrations to MRI measures, adjusting for potential confounders. RESULTS: We included 1882 participants (mean age of 48 ± 8 years, 54% women). Higher RBP4 concentrations were related to markers of brain atrophy, including smaller total (Beta ± standard error, -0.05 ± 0.02; p = 0.014) and cortical gray brain volumes (-0.06 ± 0.02; p = 0.004), and larger lateral ventricular volumes (0.06 ± 0.02; p = 0.006). Additionally, higher RBP4 (-0.06 ± 0.03; p = 0.042), Fetuin-A (-0.06 ± 0.03; p = 0.039), and FABP4 (-0.09 ± 0.03; p = 0.008) concentrations were associated with smaller anterior hippocampal volumes. Most associations remained after additional adjustment for vascular risk factors. In exploratory analyses, higher FABP4 was related to larger total brain in non-obese participants, and to smaller anterior hippocampal volumes in obese participants. Finally, higher adiponectin concentrations were related to smaller cortical gray, only in non-obese participants. CONCLUSIONS: Our results suggest that adipokines are associated with markers of brain atrophy during midlife. Further studies are needed to replicate these findings and elucidate any potential mechanisms contributing to abnormal brain aging.
Keywords: Adipokines; Adiponectin; Adult; Aging; alpha-2-HS-Glycoprotein; Atrophy; Biomarkers; Brain; Cohort Studies; Fatty Acid-Binding Proteins; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Retinol-Binding Proteins, Plasma

On the Clinimetrics of the Montreal Cognitive Assessment: Cutoff Analysis in Patients with Mild Cognitive Impairment due to Alzheimer's Disease. - Ilardi, Ciro Rosario; Menichelli, Alina; Michelutti, Marco; Cattaruzza, Tatiana; Federico, Giovanni; Salvatore, Marco; Iavarone, Alessandro; Manganotti, Paolo (J Alzheimers Dis, 2024)
BACKGROUND: In the era of disease-modifying therapies, empowering the clinical neuropsychologist's toolkit for timely identification of mild cognitive impairment (MCI) is crucial. OBJECTIVE: Here we examine the clinimetric properties of the Montreal Cognitive Assessment (MoCA) for the early diagnosis of MCI due to Alzheimer's disease (MCI-AD). METHODS: Data from 48 patients with MCI-AD and 47 healthy controls were retrospectively analyzed. Raw MoCA scores were corrected according to the conventional Nasreddine's 1-point correction and demographic adjustments derived from three normative studies. Optimal cutoffs were determined while previously established cutoffs were diagnostically reevaluated. RESULTS: The original Nasreddine's cutoff of 26 and normative cutoffs (non-parametric outer tolerance limit on the 5th percentile of demographically-adjusted score distributions) were overly imbalanced in terms of Sensitivity (Se) and Specificity (Sp). The optimal cutoff for Nasreddine's adjustment showed adequate clinimetric properties (≤23.50, Se = 0.75, Sp = 0.70). However, the optimal cutoff for Santangelo's adjustment (≤22.85, Se = 0.65, Sp = 0.87) proved to be the most effective for both screening and diagnostic purposes according to Larner's metrics. The results of post-probability analyses revealed that an individual testing positive using Santangelo's adjustment combined with a cutoff of 22.85 would have 84% post-test probability of receiving a diagnosis of MCI-AD (LR+ = 5.06). CONCLUSIONS: We found a common (mal)practice of bypassing the applicability of normative cutoffs in diagnosis-oriented clinical practice. In this study, we identified optimal cutoffs for MoCA to be allocated in secondary care settings for supporting MCI-AD diagnosis. Methodological and psychometric issues are discussed.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Retrospective Studies; Sensitivity and Specificity

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

Comparative Efficacy, Tolerability, and Acceptability of Donanemab, Lecanemab, Aducanumab, Melatonin, and Aerobic Exercise for a Short Time on Cognitive Function in Mild Cognitive Impairment and Mild Alzheimer's Disease - Terao, Itsuki; Kodama, Wakako (J Alzheimers Dis, 2024)
BACKGROUND: The Food and Drug Administration (FDA) has approved lecanemab and aducanumab and is reviewing donanemab, but they have questionable efficacy, serious side effects and are costly, whereas melatonin administration and aerobic exercise for a short time may overcome these problems. OBJECTIVE: We aim to compare the efficacy on cognitive function, tolerability and acceptability of melatonin administration and aerobic exercise for a short time with donanemab, lecanemab, and aducanumab in people with mild AD and MCI. METHODS: We systematically reviewed relevant randomized placebo-controlled trials (RCTs) in PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov and performed network meta-analyses. RESULTS: The analysis included 10 randomized placebo-controlled trials with 4,599 patients. Although melatonin and aerobic exercise for a short time were significantly more effective than donanemab, lecanemab, aducanumab and placebo in the primary analysis, there was significant heterogeneity. In the sensitivity analysis excluding exercise, melatonin was significantly more effective than donanemab, lecanemab, aducanumab and placebo, with no significant heterogeneity. Aerobic exercise for a short time was significantly less acceptable than donanemab, aducanumab and placebo. Donanemab, lecanemab, and aducanumab were significantly less tolerable than placebo and donanemab and lecanemab were significantly less acceptable than placebo. CONCLUSIONS: Melatonin may be a better potential disease-modifying treatment for cognitive decline in mild AD and MCI. Aerobic exercise for a short time might also be better than donanemab, lecanemab and aducanumab if continued, as it is well tolerated and more effective, although less valid due to heterogeneity. Another limitation is the small number of participants.
Keywords: Alzheimer Disease; Antibodies, Monoclonal, Humanized; Cognition; Cognitive Dysfunction; Exercise Therapy; Humans; Melatonin; Network Meta-Analysis; Randomized Controlled Trials as Topic; Treatment Outcome

Comprehensive Analysis of Metabolites in Postmortem Brains of Patients with Alzheimer's Disease. - Kurano, Makoto; Saito, Yuko; Yatomi, Yutaka (J Alzheimers Dis, 2024)
BACKGROUND: Disturbed metabolism has been proposed as being involved in the pathogenesis of Alzheimer's disease (AD), and more evidence from human AD brains is required. OBJECTIVE: In this study, we attempted to identify or confirm modulations in the levels of metabolites associated with AD in postmortem AD brains. METHODS: We performed metabolomics analyses using a gas chromatography mass spectrometry system in postmortem brains of patients with confirmed AD, patients with CERAD score B, and control subjects. RESULTS: Impaired phosphorylation of glucose and elevation of several tricarboxylic acid (TCA) metabolites, except citrate, were observed and the degree of impaired phosphorylation and elevation in the levels of the TCA cycle metabolites were negatively and positively correlated, respectively, with the clinical phenotypes of AD. The levels of uronic acid pathway metabolites were modulated in AD and correlated positively with the amyloid-β content. The associations of nucleic acid synthesis and amino acid metabolites with AD depended on the kinds of metabolites; in particular, the contents of ribose 5-phosphate, serine and glycine were negatively correlated, while those of ureidosuccinic acid and indole-3-acetic acid were positively modulated in AD. Comprehensive statistical analyses suggested that alterations in the inositol pathway were most closely associated with AD. CONCLUSIONS: The present study revealed many novel associations between metabolites and AD, suggesting that some of these might serve as novel potential therapeutic targets for AD.

Computational Evaluation of the Potential Pharmacological Activity of Salen-Type Ligands in Alzheimer's Disease. - Puentes-Díaz, Nicolás; Chaparro, Diego; Reyes-Marquez, Viviana; Morales-Morales, David; Flores-Gaspar, Areli; Alí-Torres, Jorge (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-β peptide (Aβ) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Chelating Agents; Computational Biology; Copper; Humans; Ligands; Oxidative Stress

A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5. - Mahzarnia, Ali; Lutz, Michael W; Badea, Alexandra (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies. OBJECTIVE: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype. METHODS: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways. RESULTS: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers. CONCLUSIONS: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2's role in AD cognition and demonstrated ITGA5's significant role in mediating the AD pathology-cognition connection.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Cognitive Dysfunction; Humans; Likelihood Functions; tau Proteins; Vascular Endothelial Growth Factor A

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

Current Status and Challenges in Dementia Care in the Philippines: A Scoping Review. - Anlacan, Veeda Michelle M; Lanuza, Pamela Danielle T; Sanchez, Anna Anjelica R; Jamora, Roland Dominic G (J Alzheimers Dis, 2024)
BACKGROUND: Dementia prevalence is increasing in low- and middle-income countries such as the Philippines. OBJECTIVE: This study aimed to give an overview of dementia care in the Philippines and to identify gaps in terms of local epidemiology, research, financial coverage, diagnostics, pharmacotherapy, manpower, and caregiver support. METHODS: This scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines extension for scoping reviews. Six international and two local databases, and government and non-government websites were searched. Data published in the English or Filipino language on dementia epidemiology, research, diagnostics, management, manpower, and training were extracted from the earliest indexed record until June 2022. RESULTS: The prevalence of dementia in the Philippines is high and research output on all aspects of dementia is low. Cost is a major barrier as health care coverage is limited, with reliance mainly on out-of-pocket payments, leading to challenges in the proper diagnosis and treatment of dementia. There is a low specialist-to-population ratio, with shortages beyond manpower and training. CONCLUSIONS: Gaps in dementia care include limited published local data, high healthcare costs, inadequate health financing, and limited manpower.
Keywords: Dementia; Health Care Costs; Health Services; Humans; Philippines; Prevalence

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

Dementia in the Ancient Greco-Roman World Was Minimally Mentioned. - Finch, Caleb E; Burstein, Stanley M (J Alzheimers Dis, 2024)
BACKGROUND: The possibility that Alzheimer's disease and related dementias (ADRD) is a modern disease arises from the minimal mention of advanced cognitive decline by ancient Greeks and Romans, who were mainly concerned with the physical frailties of older ages. OBJECTIVE: Because standard medical histories of elderly health lacked mention of cognitive decline, we examined texts by Greek and Roman authors that mentioned memory loss and dementia. METHODS: Primary texts of Greco-Roman authors, 8th century BCE into the 3rd century CE, that mentioned cognitive decline were identified and critically evaluated. Secondary sources were excluded. RESULTS: No ancient account of cognitive loss is equivalent to modern clinical data. The term dementia was occasionally used in antiquity, but not invariably linked to old age. Ancient Greeks and Romans expected intellectual competence beyond age 60. While some memory loss was acknowledged, we found only four accounts of severe cognitive loss that might represent ADRD. The possibility of modest ADRD prevalence in ancient Greece and Rome is consistent with its low prevalence in the Tsimane of Bolivia. These contemporary Amerindians live under conditions of high mortality from frequent infections and minimal cardiovascular disease with physically demanding lives. Tsimane after age 60 had increased mild cognitive impairment; the few cases of dementia were not clinically consistent with AD. CONCLUSIONS: The modern 'epidemic level' of advanced dementias was not described among ancient Greco-Roman elderly. The possible emergence of advanced ADRD in the Roman era may be associated with environmental factors of air pollution and increased exposure to lead. Further historical analysis may formulate critical hypotheses about the modernity of high ADRD prevalence.
Keywords: Aged; Alzheimer Disease; Greek World; Humans; Memory Disorders; Roman World

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.

Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer's Disease. - Weinberg, Marc S; He, Yingnan; Kivisäkk, Pia; Arnold, Steven E; Das, Sudeshna (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. OBJECTIVE: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. METHODS: We analyzed plasma and CSF proteomics data collected previously (ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. RESULTS: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. CONCLUSIONS: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Proteomics

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

Elevated Risk of Dementia Diagnosis in Older Adults with Low Frequencies and Durations of Social Conversation. - Shimada, Hiroyuki; Doi, Takehiko; Tsutsumimoto, Kota; Makino, Keitaro; Harada, Kenji; Tomida, Kouki; Arai, Hidenori (J Alzheimers Dis, 2024)
BACKGROUND: Social networks and social participation have protective effects on cognitive function maintenance and Alzheimer's disease and general dementia development. OBJECTIVE: We aimed to investigate the association between conversations and dementia incidence in older adults. METHODS: This longitudinal prospective cohort study used population data from the National Center for Geriatric and Gerontology-Study of Geriatric Syndromes (NCGG-SGS) from September 2015 to February 2017. The database included 4,167 individuals in Japan aged ≥60 years who were generally healthy and without major cognitive impairment. Participants were classified into two groups according to six daily conversation measures at baseline. The conversation index was calculated as a composite score for these measures. Participants were tracked monthly over 60 months for new-onset dementia. RESULTS: Data from 2,531 participants were analyzed (72.7±6.7 years; range: 60-96 years). Dementia incidence per 1,000 person-years was 15.7 (95% confidence interval, 13.6-18.1). The Youden index determined the cut-off point for dementia incidence, with a conversation index of 16/17 points. The low conversation group included more participants with new-onset dementia. Cox proportional hazards regression crude models showed remarkable relationships between dementia onset and specific conversation measurements, including conversation index. According to the Cox regression adjusted model, the cut-off point of the conversation index showed only a remarkable relationship with dementia onset. CONCLUSIONS: Dementia risk was extensively associated with low daily conversation statuses. The assessment of conversational factors may be useful as a risk indicator for the development of Alzheimer's disease and general dementia.
Keywords: Aged; Alzheimer Disease; Cognitive Dysfunction; Dementia; Geriatrics; Humans; Prospective Studies

Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer's Disease Models. - Liang, Xiao; Wang, Yangyang; Li, Siyu; Fan, Jianing; Zhou, Fanlin; Li, Xiaoju; Li, Shijie; Li, Yu (J Alzheimers Dis, 2024)
BACKGROUND: Mitochondrial dysfunction exists in Alzheimer's disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. OBJECTIVE: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. METHODS: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-β secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. RESULTS: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. CONCLUSIONS: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; GTPase-Activating Proteins; Humans; Male; Mice; Mice, Transgenic; Mitochondria; Mitophagy; Neurons; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins

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

Equilibrium of Dietary Patterns Between Alzheimer's Disease Patients and Healthy People: A Comprehensive Analysis Using Multiple Factor Analysis and Classification Modeling. - Ahmed, Tahera; Zhang, Ping; Kumar, Kuldeep (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a particular type of dementia that currently lacks a definitive treatment and cure. It is possible to reduce the risk of developing AD and mitigate its severity through modifications to one's lifestyle, regular diet, and alcohol-drinking habits. OBJECTIVE: The objective of this study is to examine the daily dietary patterns of individuals with AD compared to healthy controls, with a focus on nutritional balance and its impact on AD. METHODS: This study incorporated multiple-factor analysis (MFA) to evaluate dietary patterns and employed Random Forest (RF) classifier and Sparse Logistic Regression (SLR) for Variable Importance analysis to identify food items significantly associated with AD. RESULTS: MFA revealed trends in the data and a strong correlation (Lg = 0.92, RV = 0.65) between the daily consumption of processed food and meat items in AD patients. In contrast, no significant relationship was found for any daily consumed food categories within the healthy control (HC) group. Food items such as meat pie, hamburger, ham, sausages, beef, capsicum, and cabbage were identified as important variables associated with AD in RF and SLR analyses. CONCLUSIONS: The findings from MFA indicated that the diversity or equilibrium of daily diet might play a potential role in AD development. RF and SLR classifications exhibit among the processed foods, especially deli meats and food made with meat items, are associated with AD.
Keywords: Alzheimer Disease; Diet; Factor Analysis, Statistical; Humans; Vegetables

The Etiology of Rapidly Progressive Dementia: A 3-Year Retrospective Study in a Tertiary Hospital in China. - Shi, Qin; Liu, Wei-Shi; Liu, Fang; Zeng, Yi-Xuan; Chen, Shu-Fen; Chen, Ke-Liang; Yu, Jin-Tai; Huang, Yu-Yuan (J Alzheimers Dis, 2024)
BACKGROUND: Rapidly progressive dementia (RPD), characterized by a rapid cognitive decline leading to dementia, comprises a diverse range of disorders. Despite advancements in diagnosis and treatment, research on RPD primarily focuses on Western populations. OBJECTIVE: This study aims to explore the etiology and demographics of RPD in Chinese patients. METHODS: We retrospectively analyzed 323 RPD inpatients at Huashan Hospital from May 2019 to March 2023. Data on sociodemographic factors, epidemiology, clinical presentation, and etiology were collected and analyzed. RESULTS: The median onset age of RPD patients was 60.7 years. Two-thirds received a diagnosis within 6 months of symptom onset. Memory impairment was the most common initial symptom, followed by behavioral changes. Neurodegenerative diseases accounted for 47.4% of cases, with central nervous system inflammatory diseases at 30.96%. Autoimmune encephalitis was the leading cause (16.7%), followed by Alzheimer's disease (16.1%), neurosyphilis (11.8%), and Creutzfeldt-Jakob disease (9.0%). Alzheimer's disease, Creutzfeldt-Jakob disease, and frontotemporal dementia were the primary neurodegenerative causes, while autoimmune encephalitis, neurosyphilis, and vascular cognitive impairment were the main non-neurodegenerative causes. CONCLUSIONS: The etiology of RPD in Chinese patients is complex, with neurodegenerative and non-neurodegenerative diseases equally prevalent. Recognizing treatable conditions like autoimmune encephalitis and neurosyphilis requires careful consideration and differentiation.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; China; Cognitive Dysfunction; Creutzfeldt-Jakob Syndrome; Dementia; Disease Progression; Encephalitis; Female; Frontotemporal Dementia; Humans; Male; Middle Aged; Neurodegenerative Diseases; Neurosyphilis; Retrospective Studies; Tertiary Care Centers

Exploring the Genetic Heterogeneity of Alzheimer's Disease: Evidence for Genetic Subtypes. - Elman, Jeremy A; Schork, Nicholas J; Rangan, Aaditya V (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. OBJECTIVE: We investigated genetic heterogeneity in AD risk through a multi-step analysis. METHODS: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. RESULTS: PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. CONCLUSIONS: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.

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

Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease. - Moreno-Rodriguez, Marta; Perez, Sylvia E; Martinez-Gardeazabal, Jonatan; Manuel, Iván; Malek-Ahmadi, Michael; Rodríguez-Puertas, Rafael; Mufson, Elliott J (J Alzheimers Dis, 2024)
BACKGROUND: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. OBJECTIVE: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. METHODS: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). RESULTS: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. CONCLUSIONS: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Functional Connectivity Favors Aberrant Visual Network c-Fos Expression Accompanied by Cortical Synapse Loss in a Mouse Model of Alzheimer's Disease. - L'Esperance, Oliver J; McGhee, Joshua; Davidson, Garett; Niraula, Suraj; Smith, Adam S; Sosunov, Alexandre A; Yan, Shirley ShiDu; Subramanian, Jaichandar (J Alzheimers Dis, 2024)
BACKGROUND: While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. OBJECTIVE: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. METHODS: c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4-6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. RESULTS: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. CONCLUSIONS: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions.
Keywords: Alzheimer Disease; Animals; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-fos; Synapses; Visual Cortex

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

Gene Co-Expression Analysis of Multiple Brain Tissues Reveals Correlation of FAM222A Expression with Multiple Alzheimer's Disease-Related Genes. - Liang, Jingjing; LaFleur, Bonnie; Hussainy, Sadiya; Perry, George (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A, encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. OBJECTIVE: Our goal was to study FAM222A's whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. METHODS: We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed genes and performed functional enrichment analysis on identified genes in CNS system. RESULTS: Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p < 2.5×10-6) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. CONCLUSION: This gene co-expression study identified multiple AD-related genes that are associated with FAM222A, indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD.
Keywords: Aged; Alzheimer Disease; Brain; Female; Gene Expression Profiling; Genome-Wide Association Study; Humans; Male

Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study. - Vestin, Erika; Boström, Gustaf; Olsson, Jan; Elgh, Fredrik; Lind, Lars; Kilander, Lena; Lövheim, Hugo; Weidung, Bodil (J Alzheimers Dis, 2024)
BACKGROUND: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ɛ4 carriership interaction. METHODS: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. RESULTS: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1. CONCLUSIONS: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

High-Fat Diets in Animal Models of Alzheimer's Disease: How Can Eating Too Much Fat Increase Alzheimer's Disease Risk? - Valentin-Escalera, Josue; Leclerc, Manon; Calon, Frederic (J Alzheimers Dis, 2024)
High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Mice; Mice, Transgenic

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.

Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease. - Uh, Kyungjun; Monarch, Kaylynn; Reese, Emily D; Rodriguez, Katherine; Yoon, Junchul; Spate, Lee D; Samuel, Melissa S; Koh, Sehwon; Chen, Paula R; Jarome, Timothy J; Allen, Timothy A; Prather, Randall S; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. OBJECTIVE: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. METHODS: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. RESULTS: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases. CONCLUSIONS: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease.

Improving Healthcare Quality and Clinical Outcomes for Persons with Dementia in the Sub-Acute Hospital Through Person-Centered Care Practice. - Chenoweth, Lynn; Burley, Claire; Cook, Jacquelene; Cheah, Seong-Leang; Reyes, Patricia; Maiden, Genevieve; McGuire, Jane; McCade, Donna; Brodaty, Henry; Sukhapure, Mayouri; Harrison, Fleur; Williams, Anna (J Alzheimers Dis, 2024)
BACKGROUND: Person-centered care is considered beneficial for persons with dementia. OBJECTIVE: To evaluate the impact of a person-centered knowledge translation intervention on the quality of healthcare and outcomes for persons with dementia. METHODS: Over nine months, sub-acute hospital nursing, allied health, and medical staff (n = 90) participated in online and/or face-to-face person-centered education and were supported by senior nursing, allied health, and medical staff champions (n = 8) to implement person-centered healthcare. The quality of healthcare service, ward climate and care delivery were evaluated pre/post study intervention. In the week following hospital admission (Time 1) and week of discharge (Time 3), agitation incidence (co-primary outcome) was assessed in participants with dementia (n = 80). Participant delirium (co-primary outcome), accidents/injuries, psychotropic medicines, length of stay, readmission and discharge destination (secondary outcomes) were compared with a retrospective group (n = 77) matched on demographics, cognition and function in activities of daily living. RESULTS: Improvements occurred post-intervention in service quality by 17.5% (p = 0.369, phi = 0.08), ward climate by 18.1% (p = 0.291, phi = 0.08), and care quality by 50% (p = 0.000, phi = 0.37). Participant agitation did not change from Time 1 to Time 3 (p = 0.223). Relative to the retrospective group, significant reductions occurred in participant delirium (p = 0.000, phi = 0.73), incidents/injuries (p = 0.000, phi = 0.99), psychotropic medicine use (p = 0.030, phi = 0.09), and hospital readmissions within 30 days (p = 0.002, phi = 0.25), but not in discharge to home (p = 0.171). CONCLUSIONS: When person-centered healthcare knowledge is translated through staff education and practice support, persons with dementia can experience improved healthcare services and clinical outcomes, while healthcare services can benefit through reductions in unplanned service use.

The Inflammation-Induced Dysregulation of Reelin Homeostasis Hypothesis of Alzheimer's Disease. - Reive, Brady S; Lau, Victor; Sánchez-Lafuente, Carla L; Henri-Bhargava, Alexandre; Kalynchuk, Lisa E; Tremblay, Marie-Ève; Caruncho, Hector J (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation.
Keywords: Alzheimer Disease; Animals; Cell Adhesion Molecules, Neuronal; Extracellular Matrix Proteins; Homeostasis; Humans; Inflammation; Nerve Tissue Proteins; Reelin Protein; Serine Endopeptidases; Signal Transduction

Influence of genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum. - Papotti, Bianca; Palumbo, Marcella; Adorni, Maria Pia; Elviri, Lisa; Chiari, Annalisa; Tondelli, Manuela; Bedin, Roberta; Baldelli, Enrica; Lancellotti, Giulia; Lupo, Maria Giovanna; Ferri, Nicola; Bertolotti, Marco; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the genotype are not clarified. OBJECTIVE: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the genotype. METHODS: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. RESULTS: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD carriers showed higher PCSK9 and 24-HC (+61.3%,  = 0.027 and +32.7%,  = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444,  = 0.049) and, exclusively among AD carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786,  = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520,  = 0.004), driven by carriers (r = 0.544,  = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465,  = 0.039) in AD. None of these results were found in MCI-AD patients. CONCLUSIONS: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Biomarkers; Cholesterol; Cognitive Dysfunction; Female; Genotype; Humans; Lipids; Male; Middle Aged; Proprotein Convertase 9

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

Interaction Between Arteriosclerosis and Amyloid-β on Cognitive Function. - Frentz, Ingeborg; van Arendonk, Joyce; Leeuwis, Anna E; Vernooij, Meike W; van der Flier, Wiesje M; Bos, Daniel; De Deyn, Peter Paul; Wolters, Frank J; Ikram, M Arfan (J Alzheimers Dis, 2024)
BACKGROUND: Dementia is a multifactorial disease, with Alzheimer's disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. OBJECTIVE: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. METHODS: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. RESULTS: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. CONCLUSIONS: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Arteriosclerosis; Biomarkers; Cognition; Cognitive Dysfunction; Female; Humans; Male; tau Proteins

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.

Long-Term Safety of Gantenerumab in Participants with Alzheimer's Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD). - Neve, Anuja; Das, Bibha; Wojtowicz, Jakub; Huang, Zhiyue; Bullain, Szofia; Watkin, Michelle; Lott, Dominik; Bittner, Tobias; Delmar, Paul; Klein, Gregory; Hofmann, Carsten; Kerchner, Geoffrey A; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer's disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE). OBJECTIVE: The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants. METHODS: Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. RESULTS: Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings. CONCLUSIONS: SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains. - Zhang, Xiaoyu; Haeri, Mohammad; Swerdlow, Russell H; Wang, Ning (J Alzheimers Dis, 2024)
BACKGROUND: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. OBJECTIVE: To characterize how AD impacts adaptive DNA breaks at nervous system genes. METHODS: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. RESULTS: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. CONCLUSIONS: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.

Lucidity in the Deeply Forgetful: A Scoping Review. - Ross, John Paul; Post, Stephen G; Scheinfeld, Laurel (J Alzheimers Dis, 2024)
BACKGROUND: Even in severe states of Alzheimer's disease and related dementias (ADRD), accounts of an unexpected or paradoxical return of awareness and lucidity have been reported in some patients, documented formally, and studied. OBJECTIVE: A scoping review was undertaken to survey the literature on the topic. METHODS: Five databases were searched using pertinent search terms. Results were deduplicated and subsequently screened by title and abstract for relevance. Remaining reports were read and included or excluded using specific inclusion criteria. 30 results consisted of a mix of perspective papers, case reports, qualitative surveys of caregivers, law journal comments, and mechanistic speculation. RESULTS: An equal mix of primary and secondary research was identified. CONCLUSIONS: The papers collected in this review provide a valuable methodological outline for researching the topic of lucid episodes in ADRD. The verified legitimacy and simultaneous inexplicability of these events promote philosophical discussion, mechanistic investigations, and sorely needed research in the field of ADRD.
Keywords: Alzheimer Disease; Caregivers; Cognition; Humans

Markers of amyloid-β deposition and burden of enlarged perivascular spaces in patients with cognitive impairment and small vessel disease. - Costa, Ana Sofia; Exalto, Lieza G; van der Flier, Wiesje M; Teunissen, Charlotte E; Barkhof, Frederik; Kuijf, Hugo J; Biessels, Geert Jan (J Alzheimers Dis, 2024)
MRI-visible enlarged perivascular spaces (EPVS) are common in patients with cognitive impairment and possibly linked to Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In a study of memory clinic patients (n = 450; mean age 66.5 ± 7.45, 45.8% female), we investigated CSF amyloid-β (Aβ) (AD biomarker) and strictly lobar microbleeds (CAA marker) in relation to centrum semiovale EPVS (CSO-EPVS). Age-controlled analyses showed that severe CSO-EPVS associated with Aβ status (odds ratio [OR] = 1.51, 95%CI = 1.02-2.24), but not strictly lobar microbleeds (OR = 1.39, 95%CI = 0.92-2.11), with no significant Aβ status and microbleeds interaction. This implies that in this setting, severe CSO-EPVS is not a specific indicator of CAA.

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.

Memory consolidation, temporal and parietal atrophy, and metabolism in amyloid-β positive and negative mild cognitive impairment. - Keith, Cierra M; Haut, Marc W; Vieira Ligo Teixeira, Camila; Mehta, Rashi I; Phelps, Holly; Ward, Melanie; Miller, Mark; Navia, R Osvaldo; Coleman, Michelle M; Marano, Gary; Wang, Xiaofei; Pockl, Stephanie; et al. (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is classically characterized by alterations in memory consolidation. With the advent of diagnostic biomarkers, some patients clinically diagnosed with AD display biomarkers inconsistent with the diagnosis. OBJECTIVE: We aimed to explore differences in memory consolidation and neurodegeneration of the temporal and parietal lobes as a function of amyloid-β status in amnestic mild cognitive impairment (aMCI). METHODS: We examined differences in memory consolidation and neurodegeneration between patients diagnosed with amyloid-β positive aMCI (Aβ+ N = 78), amyloid-β negative aMCI (Aβ- N = 48), and healthy participants (HP; N = 41), within a well-characterized clinical cohort. RESULTS: Aβ+ exhibited more pronounced consolidation impairments compared to Aβ-, while Aβ- faced more consolidation challenges than HP. Both Aβ+ and Aβ- were similar in hippocampal volume and entorhinal thickness, but Aβ+ had thinner inferior parietal cortex than Aβ-. Using F-fluoro-deoxyglucose-positron emission tomography, metabolism in both temporal and parietal regions was lower in Aβ+ relative to Aβ-. CONCLUSIONS: These findings suggest pathologies other than AD likely contribute to memory consolidation difficulties in aMCI, and neurodegeneration of the parietal cortex in combination with hypometabolism may contribute to more pronounced consolidation problems in Aβ+.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Atrophy; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Memory Consolidation; Middle Aged; Neuropsychological Tests; Parietal Lobe; Positron-Emission Tomography; Temporal Lobe

Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease. - Ramadan, Ferris A; Arani, Gayatri; Jafri, Ayan; Thompson, Tingting; Bland, Victoria L; Renquist, Benjamin; Raichlen, David A; Alexander, Gene E; Klimentidis, Yann C (J Alzheimers Dis, 2024)
BACKGROUND: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. OBJECTIVE: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. METHODS: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). RESULTS: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. CONCLUSIONS: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

A Metabolomics Analysis of a Novel Phenotype of Older Adults at Higher Risk of Dementia. - Sultana, Munira; Camicioli, Richard; Dixon, Roger A; Whitehead, Shawn; Pieruccini-Faria, Frederico; Petrotchenko, Evgeniy; Speechley, Mark; Borchers, Christoph H; Montero-Odasso, Manuel (J Alzheimers Dis, 2024)
BACKGROUND: Older adults presenting with dual-decline in cognition and walking speed face a 6-fold higher risk for dementia compared with those showing no decline. We hypothesized that the metabolomics profile of dual-decliners would be unique even before they show signs of decline in cognition and gait speed. OBJECTIVE: The objective of this study was to determine if plasma metabolomics signatures can discriminate dual-decliners from no decliners, purely cognitive decliners, and purely motor decliners prior to decline. METHODS: A retrospective cross-sectional study using baseline plasma for untargeted metabolomics analyses to investigate early signals of later dual-decline status in study participants (n = 76) with convenient sampling. Dual-decline was operationalized as decline in gait speed (>10 cm/s) and cognition (>2 points decline in Montreal Cognitive Assessment score) on at least two consecutive 6-monthly assessments. The participants' decliner status was evaluated 3 years after the blood sample was collected. Pair-wise comparison of detected compounds was completed using principal components and hierarchical clustering analyses. RESULTS: Analyses did not detect any cluster separation in untargeted metabolomes across baseline groups. However, follow-up analyses of specific molecules detected 4 compounds (17-Hydroxy-12-(hydroxymethyl)-10-oxo-8 oxapentacyclomethyl hexopyranoside, Fleroxacin, Oleic acid, and 5xi-11,12-Dihydroxyabieta-8(14),9(11),12-trien-20-oic acid) were at significantly higher concentration among the dual-decliners compared to non-decliners. The pure cognitive decliner group had significantly lower concentration of six compounds (1,3-nonanediol acetate, 4-(2-carboxyethyl)-2-methoxyphenyl beta-D-glucopyranosiduronic acid, oleic acid, 2E-3-[4-(sulfo-oxy)phenyl] acrylic acid, palmitelaidic acid, and myristoleic acid) compared to the non-decliner group. CONCLUSIONS: The unique metabolomics profile of dual-decliners warrants follow-up metabolomics analysis. Results may point to modifiable pathways.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Female; Humans; Male; Metabolomics; Phenotype; Retrospective Studies

Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer's Disease. - Li, Yunfeng; Chen, Xiongjin; Zhou, Mulan; Feng, Sifan; Peng, Xiaoping; Wang, Yan (J Alzheimers Dis, 2024)
Alzheimer's disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer's disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Humans; Inflammasomes; Microglia; Neurodegenerative Diseases; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Toll-Like Receptor 4

Mitochondria-Related Candidate Genes and Diagnostic Model to Predict Late-Onset Alzheimer's Disease and Mild Cognitive Impairment. - Yan, Ran; Wang, Wenjing; Yang, Wen; Huang, Masha; Xu, Wei (J Alzheimers Dis, 2024)
BACKGROUND: Late-onset Alzheimer's disease (LOAD) is the most common type of dementia, but its pathogenesis remains unclear, and there is a lack of simple and convenient early diagnostic markers to predict the occurrence. OBJECTIVE: Our study aimed to identify diagnostic candidate genes to predict LOAD by machine learning methods. METHODS: Three publicly available datasets from the Gene Expression Omnibus (GEO) database containing peripheral blood gene expression data for LOAD, mild cognitive impairment (MCI), and controls (CN) were downloaded. Differential expression analysis, the least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination (SVM-RFE) were used to identify LOAD diagnostic candidate genes. These candidate genes were then validated in the validation group and clinical samples, and a LOAD prediction model was established. RESULTS: LASSO and SVM-RFE analyses identified 3 mitochondria-related genes (MRGs) as candidate genes, including NDUFA1, NDUFS5, and NDUFB3. In the verification of 3 MRGs, the AUC values showed that NDUFA1, NDUFS5 had better predictability. We also verified the candidate MRGs in MCI groups, the AUC values showed good performance. We then used NDUFA1, NDUFS5 and age to build a LOAD diagnostic model and AUC was 0.723. Results of qRT-PCR experiments with clinical blood samples showed that the three candidate genes were expressed significantly lower in the LOAD and MCI groups when compared to CN. CONCLUSION: Two mitochondrial-related candidate genes, NDUFA1 and NDUFS5, were identified as diagnostic markers for LOAD and MCI. Combining these two candidate genes with age, a LOAD diagnostic prediction model was successfully constructed.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Male; Mitochondria; Support Vector Machine

Music Therapy as a Complementary Treatment in Patients with Dementia Associated to Alzheimer's Disease: A Systematic Review. - Rossi, Eleonora; Marrosu, Francesco; Saba, Luca (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is a complex condition that affects various aspects of a patient's life. Music therapy may be considered a beneficial supplementary tool to traditional therapies, that not fully address the range of AD manifestations. OBJECTIVE: The purpose of this systematic review is to investigate whether music therapy can have a positive impact on AD patients and on which symptoms. METHODS: The main research databases employed have been PubMed and Cochrane, using the keywords "dementia", "music therapy", "Alzheimer", "fMRI", "music", and "EEG". RESULTS: After removing duplicates and irrelevant studies, 23 were screened using set criteria, resulting in the final inclusion of 15 studies. The total number of participants included in these studies has been of 1,196 patients. For the fMRI analysis the search resulted in 28 studies on PubMed, two of which were included in the research; the total number of participants was of 124 individuals. The studies conducted with EEG were found using PubMed. The initial search resulted in 15 studies, but after a more accurate evaluation only 2 have been included in the analysis. CONCLUSIONS: Even though the data currently available is not sufficient to draw conclusions supported by robust statistical power, the impact of music therapy on AD neuropsychiatric symptoms deserves great interest. Further research should be ushered, possibly multicentric studies, led with neuroimaging and other recent techniques, which can eventually open views on the music role in improving the cognitive status in AD.
Keywords: Alzheimer Disease; Humans; Music Therapy

Network Hyperexcitability in Early-Stage Alzheimer's Disease: Evaluation of Functional Connectivity Biomarkers in a Computational Disease Model. - Stam, Cornelis Jan; de Haan, Willem (J Alzheimers Dis, 2024)
BACKGROUND: There is increasing evidence from animal and clinical studies that network hyperexcitability (NH) may be an important pathophysiological process and potential target for treatment in early Alzheimer's disease (AD). Measures of functional connectivity (FC) have been proposed as promising biomarkers for NH, but it is unknown which measure has the highest sensitivity for early-stage changes in the excitation/inhibition balance. OBJECTIVE: We aim to test the performance of different FC measures in detecting NH at the earliest stage using a computational approach. METHODS: We use a whole brain computational model of activity dependent degeneration to simulate progressive AD pathology and NH. We investigate if and at what stage four measures of FC (amplitude envelope correlation corrected [AECc], phase lag index [PLI], joint permutation entropy [JPE] and a new measure: phase lag time [PLT]) can detect early-stage AD pathophysiology. RESULTS: The activity dependent degeneration model replicates spectral changes in line with clinical data and demonstrates increasing NH. Compared to relative theta power as a gold standard the AECc and PLI are shown to be less sensitive in detecting early-stage NH and AD-related neurophysiological abnormalities, while the JPE and the PLT show more sensitivity with excellent test characteristics. CONCLUSIONS: Novel FC measures, which are better in detecting rapid fluctuations in neural activity and connectivity, may be superior to well-known measures such as the AECc and PLI in detecting early phase neurophysiological abnormalities and in particular NH in AD. These markers could improve early diagnosis and treatment target identification.

Neural Computation-Based Methods for the Early Diagnosis and Prognosis of Alzheimer's Disease Not Using Neuroimaging Biomarkers: A Systematic Review. - Cabrera-León, Ylermi; Báez, Patricio García; Fernández-López, Pablo; Suárez-Araujo, Carmen Paz (J Alzheimers Dis, 2024)
BACKGROUND: The growing number of older adults in recent decades has led to more prevalent geriatric diseases, such as strokes and dementia. Therefore, Alzheimer's disease (AD), as the most common type of dementia, has become more frequent too. BACKGROUND: Objective: The goals of this work are to present state-of-the-art studies focused on the automatic diagnosis and prognosis of AD and its early stages, mainly mild cognitive impairment, and predicting how the research on this topic may change in the future. METHODS: Articles found in the existing literature needed to fulfill several selection criteria. Among others, their classification methods were based on artificial neural networks (ANNs), including deep learning, and data not from brain signals or neuroimaging techniques were used. Considering our selection criteria, 42 articles published in the last decade were finally selected. RESULTS: The most medically significant results are shown. Similar quantities of articles based on shallow and deep ANNs were found. Recurrent neural networks and transformers were common with speech or in longitudinal studies. Convolutional neural networks (CNNs) were popular with gait or combined with others in modular approaches. Above one third of the cross-sectional studies utilized multimodal data. Non-public datasets were frequently used in cross-sectional studies, whereas the opposite in longitudinal ones. The most popular databases were indicated, which will be helpful for future researchers in this field. CONCLUSIONS: The introduction of CNNs in the last decade and their superb results with neuroimaging data did not negatively affect the usage of other modalities. In fact, new ones emerged.
Keywords: Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Deep Learning; Early Diagnosis; Humans; Neural Networks, Computer; Neuroimaging; Prognosis

The Neuro-Inflammatory Microenvironment: An Important Regulator of Stem Cell Survival in Alzheimer's Disease. - Shen, Zhiwei; Yang, Xinyi; Lan, Yulong; Chen, Gao (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no "curative" drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα, CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ, CSF1R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cell Survival; Humans; Inflammation; Microglia; Neurodegenerative Diseases

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

O-GlcNAcylation and Its Roles in Neurodegenerative Diseases. - Du, Pengyang; Zhang, Xiaomin; Lian, Xia; Holscher, Christian; Xue, Guofang (J Alzheimers Dis, 2024)
As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.
Keywords: Acetylglucosamine; Alzheimer Disease; Disease Progression; Humans; N-Acetylglucosaminyltransferases; Neurodegenerative Diseases; Protein Processing, Post-Translational; Proteins

Olfactory Dysfunction and Alzheimer's Disease: A Review. - McLaren, Alexandra M R; Kawaja, Michael D (J Alzheimers Dis, 2024)
Alzheimer's disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer's disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer's disease. While a correlation between olfactory dysfunction and Alzheimer's disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer's disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer's disease including amyloid-β protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Humans; Mutation; Olfaction Disorders; Presenilin-1

Optimizing the Implementation of a Lifestyle Dementia Prevention Intervention for Older Patients in an Academic Healthcare System. - Mace, Ryan A; Lyons, Christopher; Cohen, Joshua E; Ritchie, Christine; Bartels, Stephen; Okereke, Olivia I; Hoeppner, Bettina B; Brewer, Judson A; Vranceanu, Ana-Maria (J Alzheimers Dis, 2024)
BACKGROUND: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. OBJECTIVE: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. METHODS: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor's framework). RESULTS: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of "worried well," doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying "champions," and integrating with workflows and resources. CONCLUSIONS: The results will inform our recruitment, enrollment, and retention procedures to implement the first randomized clinical trial of My Healthy Brain. Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings.
Keywords: Academic Medical Centers; Aged; Alzheimer Disease; Cognitive Dysfunction; Dementia; Female; Focus Groups; Health Personnel; Humans; Life Style; Male

Palliative Care in Nursing Home Residents with Young-Onset Dementia: Professional and Family Caregiver Perspectives. - Maters, Jasper; van der Steen, Jenny T; de Vugt, Marjolein E; Bakker, Christian; Koopmans, Raymond T C M (J Alzheimers Dis, 2024)
BACKGROUND: The evidence underpinning palliative care in dementia is mostly based on research in older populations. Little is known about the palliative care needs of people with young-onset dementia (YOD). OBJECTIVE: To describe palliative care practices including advance care planning (ACP) in people with YOD residing in Dutch nursing homes. METHODS: The study presents baseline questionnaire data from an observational cohort study. Physicians, family caregivers, and nursing staff completed questionnaires about 185 residents with YOD. The questionnaires included items on sociodemographics, quality of life measured with the quality of life in late-stage dementia (QUALID) scale, dementia-related somatic health problems, symptoms, pain medication, psychotropic drugs, and ACP. RESULTS: The mean age was 63.9 (SD 5.8) years. Half (50.3%) of them were female. Alzheimer's disease dementia (42.2%) was the most prevalent subtype. The mean QUALID score was 24.0 (SD 7.9) as assessed by family caregivers, and 25.3 (SD 8.6) as assessed by the nursing staff. Swallowing problems were the most prevalent dementia-related health problem (11.4%). Agitation was often reported by physicians (42.0%) and nursing staff (40.5%). Psychotropics were prescribed frequently (72.3%). A minority had written advance directives (5.4%) or documentation on treatment preferences by the former general practitioner (27.2%). Global care goals most often focused on comfort (73.9%). Proportions of do-not-treat orders were higher than do-treat orders for all interventions except for hospitalization and antibiotics. CONCLUSIONS: ACP must be initiated earlier, before nursing home admission. A palliative approach seems appropriate even though residents are relatively young and experience few dementia-related health problems.
Keywords: Aged; Alzheimer Disease; Caregivers; Dementia; Female; Humans; Male; Nursing Homes; Palliative Care; Quality of Life

Parkinson's Disease and Other Alzheimer's Disease and Related Dementia Pathologies and the Progression of Parkinsonism in Older Adults. - Buchman, Aron S; Yu, Lei; Oveisgharan, Shahram; Zammit, Andrea R; Wang, Tianhao; Shulman, Joshua M; VanderHorst, Veronique; Nag, Sukrit; Bennett, David A (J Alzheimers Dis, 2024)
BACKGROUND: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear. OBJECTIVE: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. METHODS: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. RESULTS: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. CONCLUSIONS: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD.

Pharmacodynamic and Clinical Effects of Ginkgo Biloba Extract EGb 761 and Its Phytochemical Components in Alzheimer's Disease. - Morató, Xavier; Tartari, Juan Pablo; Pytel, Vanesa; Boada, Merce (J Alzheimers Dis, 2024)
Extracts made from plants are complex mixtures of substances with varying compositions depending on the plant material and method of manufacture. This complexity makes it difficult for scientists and clinicians to interpret findings from pharmacological and clinical research. We performed a narrative review summarizing information on ginkgo biloba leaf extract, its composition, pharmacological data and clinical evidence supporting its administration for the treatment of Alzheimer's disease (AD). Medicinal products containing ginkgo biloba leaf extract which are manufactured in compliance with the requirements of the European Pharmacopoeia are approved as medicinal products for the treatment of dementia and related conditions by drug regulatory agencies in Europe, Asia and South America. As multicomponent mixtures, they may affect various targets in the pathogenesis of AD, the most common form of dementia. Pharmacodynamic studies demonstrate the effects of EGb 761 and individual constituents on various pathophysiological features of experimentally induced cognitive impairment and neurodegeneration that could contribute to its clinical efficacy. The safety and efficacy in the treatment of AD and cognitive decline has been studied in randomized, placebo-controlled clinical trials. Most of the studies that investigate the effects of ginkgo biloba extract (GbE) used the special extract EGb 761, which makes it the best-researched plant preparation worldwide. It is therefore the only herbal alternative to standard-of-care anti-dementia drugs. However, the mechanism of action has not been fully elucidated yet, and the clinical studies in AD show heterogeneity.
Keywords: Alzheimer Disease; Animals; Ginkgo biloba; Ginkgo Extract; Humans; Phytotherapy; Plant Extracts

Pharmacologic and Nutritional Interventions for Early Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. - Zeng, Baoqi; Tang, Chunbian; Wang, Junjian; Yang, Qingqing; Ren, Qingcuo; Liu, Xiaozhi (J Alzheimers Dis, 2024)
BACKGROUND: Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD). OBJECTIVE: We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD. METHODS: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence. RESULTS: Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments- ranging from low to high certainty- showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] -0.239, 95% confidence interval [CI] -0.343 to -0.134) and lecanemab (SMD -0.194, 95% CI -0.279 to -0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo. CONCLUSIONS: Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD.
Keywords: Alzheimer Disease; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic

Plasma BDNF/Irisin Ratio Associates with Cognitive Function in Older People. - Huang, Xiuxiu; Wang, Jiaxin; Zhang, Shifang; Zhao, Xiaoyan; An, Ran; Lan, Yue; Yi, Ming; Wan, Qiaoqin (J Alzheimers Dis, 2024)
BACKGROUND: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer's disease and other dementias. OBJECTIVE: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance. METHODS: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment. RESULTS: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed. CONCLUSIONS: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance.
Keywords: Aged; Aged, 80 and over; Aging; Biomarkers; Brain-Derived Neurotrophic Factor; Clusterin; Cognition; Cognitive Dysfunction; Cross-Sectional Studies; Female; Fibronectins; Humans; Male; Mental Status and Dementia Tests; Neuropsychological Tests

Potential Impact of Slowing Disease Progression in Early Symptomatic Alzheimer's Disease on Patient Quality of Life, Caregiver Time, and Total Societal Costs: Estimates Based on Findings from GERAS-US Study. - Chandler, Julie M; Ye, Wenyu; Mi, Xiaojuan; Doty, Erin G; Johnston, Joseph A (J Alzheimers Dis, 2024)
BACKGROUND: Impact of Alzheimer's disease (AD) progression on patient health-related quality of life (HRQoL), caregiver time, and societal costs is not well characterized in early AD. OBJECTIVE: To assess the association of change in cognition with HRQoL, caregiver time, and societal costs over 36 months, and estimate the impact of slowing disease progression on these outcomes. METHODS: This post-hoc analysis included patients with amyloid-positive mild cognitive impairment (MCI) and mild AD dementia (MILD AD) from the 36-month GERAS-US study. Disease progression was assessed using the Mini-Mental State Examination score. Change in outcomes associated with slowing AD progression was estimated using coefficients from generalized linear models. RESULTS: At baseline, 300 patients had MCI and 317 had MILD AD. Observed natural progression over 36 months was associated with: 5.1 point decline in the Bath Assessment of Subjective Quality of Life in Dementia (BASQID) score (for HRQoL), increase in 1,050 hours of total caregiver time, and $8,504 total societal costs for MCI; 6.6 point decline in the BASQID score, increase in 1,929 hours of total caregiver time, and $12,795 total societal costs for MILD AD per person. Slowing AD progression by 30% could result in per person savings in HRQoL decline, total caregiver time, and total societal costs: for MCI: 1.5 points, 315 hours, and $2,638; for MILD AD: 2.0 points, 579 hours, and $3,974. CONCLUSIONS: Slowing AD progression over 36 months could slow decline in HRQoL and save caregiver time and societal cost in patients with MCI and MILD AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cognitive Dysfunction; Cost of Illness; Disease Progression; Female; Humans; Male; Mental Status and Dementia Tests; Quality of Life; United States

Pre-existing dementia is associated with 2-3 folds risk for in-hospital mortality and complications after intracerebral hemorrhage stroke. - Zuo, Lijun; Hu, Yang; Dong, YanHong; Seet, Raymond Cs; Li, Zixiao; Wang, Yongjun; Zhao, Xingquan (J Alzheimers Dis, 2024)
BACKGROUND: Pre-existing dementia was related to poor functional outcome after intracerebral hemorrhage (ICH), and its commonly underlying pathologies were considered as cerebral amyloid angiopathy. But the impact of pre-existing dementia on in-hospital mortality in Chinese ICH patients has not been well characterized. OBJECTIVE: To investigate the association between pre-existing dementia and in-hospital mortality after ICH. METHODS: Data were extracted from the China Stroke Center Alliance database. Information about the existence of prior to stroke dementia was obtained from next of kin informants and registered in clinical charts. Patients' characteristics, in-hospital mortality, home discharge and complications were compared between ICH patients with and without pre-existing dementia. RESULTS: Out of the 72,318 ICH patients, we identified 328 patients with pre-existing dementia. Patients with pre-existing dementia were more likely to experience greater stroke severity as measured by the National Institute of Health Stroke Scale and Glasgow Coma Scale. In the adjusted models, the presence of pre-existing dementia was associated with an increased risk of in-hospital mortality (OR 2.31, 95% CI 1.12-4.77), more frequent in-hospital complications of pulmonary embolism (OR 5.41, 95% CI 1.16-25.14), pneumonia (OR 1.58, 95% CI 1.08-2.33), urinary tract infection (OR 2.37, 95% CI 1.21-4.64), gastrointestinal bleeding (OR 2.39, 95% CI 1.27-4.49) and lower home discharge (OR 0.59, 95% CI 0.38∼0.93). CONCLUSIONS: ICH patients with pre-existing dementia are more likely to suffer from greater stroke severity, poorer outcomes and lower home discharge. Future studies should evaluate the value of intensive risk factor control among individuals with pre-existing dementia for stroke prevention.
Keywords: Aged; Aged, 80 and over; Cerebral Hemorrhage; China; Dementia; Female; Hemorrhagic Stroke; Hospital Mortality; Humans; Male; Middle Aged; Risk Factors; Stroke

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

Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review. - Cressot, Coralie; Vrillon, Agathe; Lilamand, Matthieu; Francisque, Hélène; Méauzoone, Aurélie; Hourregue, Claire; Dumurgier, Julien; Marlinge, Emeline; Paquet, Claire; Cognat, Emmanuel (J Alzheimers Dis, 2024)
BACKGROUND: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. OBJECTIVE: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. METHODS: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). RESULTS: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. CONCLUSIONS: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.
Keywords: Alzheimer Disease; Delusions; Dementia; Frontotemporal Dementia; Humans; Lewy Body Disease; Neurodegenerative Diseases; Psychotic Disorders

Quantitative Metabolomic Analysis of the Rat Hippocampus: Effects of Age and of the Development of Alzheimer's Disease-Like Pathology. - Snytnikova, Olga; Telegina, Darya; Savina, Ekaterina; Tsentalovich, Yuri; Kolosova, Nataliya (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease. OBJECTIVE: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs. METHODS: High resolution 1H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the "preclinical" period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control. RESULTS: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups. CONCLUSIONS: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans.
Keywords: Aging; Alzheimer Disease; Animals; Disease Models, Animal; Hippocampus; Inositol; Magnetic Resonance Spectroscopy; Male; Metabolomics; Proton Magnetic Resonance Spectroscopy; Rats; Rats, Wistar

Recalibrating the Risk-Benefit Profiles of Lecanemab and Donanemab: Scales, Immunoreactivity, and Changes in Amyloid-β42. - Espay, Alberto J; Herrup, Karl; Imbimbo, Bruno P; Kepp, Kasper P; Daly, Timothy (J Alzheimers Dis, 2024)
Three recent anti-amyloid-β antibody trials for Alzheimer's disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond removing amyloid.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Peptide Fragments; Risk Assessment

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

Regional differences in glucose metabolic decline and tau deposition in the Alzheimer's continuum brain. - Ishii, Kazunari; Yamada, Takahiro; Hanaoka, Kohei; Kaida, Hayato; Kojita, Yasuyuki; Kono, Atsushi; Hanada, Kazushi; Saigoh, Kazumasa; Sakuta, Shizuka; Hashimoto, Mamoru; Kato, Takashi; Nakamura, Akinori (J Alzheimers Dis, 2024)
BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. OBJECTIVE: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. METHODS: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. RESULTS: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. CONCLUSIONS: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Glucose; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; tau Proteins

Research Participants' Perspectives on Precision Diagnostics for Alzheimer's Disease. - Smith, Hadley Stevens; Robinson, Jill O; Levchenko, Ariel; Pereira, Stacey; Pascual, Belen; Bradbury, Kathleen; Arbones, Victoria; Fong, Jamie; Shulman, Joshua M; McGuire, Amy L; Masdeu, Joseph (J Alzheimers Dis, 2024)
BACKGROUND: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. OBJECTIVE: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. METHODS: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher's exact test and qualitatively coded open-ended responses. RESULTS: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n = 25) reported feelings of relief (Fisher's exact p < 0.001) and happiness (p < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). CONCLUSIONS: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high.
Keywords: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Cognitive Dysfunction; Emotions; Humans; Positron-Emission Tomography

The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug. - Marr, Calum; McDowell, Bethany; Holmes, Clive; Edwards, Christopher J; Cardwell, Christopher; McHenry, Michelle; Meenagh, Gary; Teeling, Jessica L; McGuinness, Bernadette (J Alzheimers Dis, 2024)
BACKGROUND: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation. OBJECTIVE: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). METHODS: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). RESULTS: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = -1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = -0.4, 1.3). CONCLUSIONS: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.
Keywords: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cognitive Dysfunction; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

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.

The Role of Impaired Receptor Trafficking in Mediating the Pathological Effects of APOE4 in Alzheimer's Disease. - Safieh, Mirna; Liraz, Ori; Ovadia, Maayan; Michaelson, Danny (J Alzheimers Dis, 2024)
BACKGROUND: Apolipoprotein E4 (APOE4) is the most prevalent genetic risk factor of Alzheimer's disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR). OBJECTIVE: To examine the effects of APOE genotype on receptors protein levels and compartmentalization. METHODS: Primary mouse neurons were prepared from APOE3 or APOE4 targeted replacement mice, or APOE-KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors' colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors. RESULTS: Our results revealed lower receptors' levels in APOE4, specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes. CONCLUSIONS: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes.
Keywords: Alzheimer Disease; Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Mice; Mice, Transgenic

Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study. - Alva, Gus; Cubała, Wiesław J; Berrio, Ana; Coate, Bruce; Abler, Victor; Pathak, Sanjeev (J Alzheimers Dis, 2024)
BACKGROUND: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer's disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. OBJECTIVE: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. METHODS: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. RESULTS: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. CONCLUSIONS: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP.
Keywords: Aged; Antipsychotic Agents; Drug Inverse Agonism; Hallucinations; Humans; Neurodegenerative Diseases; Piperidines; Psychotic Disorders; Urea

A Scoping Review of Alzheimers Disease Hypotheses: An Array of Uni- and Multi-Factorial Theories. - Duchesne, Simon; Rousseau, Louis-Simon; Belzile-Marsolais, Florence; Welch, Laurie-Ann; Cournoyer, Béatrice; Arseneau, Marianne; Lapierre, Véronick; Poulin, Sara-Maude; Potvin, Olivier; Hudon, Carol (J Alzheimers Dis, 2024)
BACKGROUND: There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. OBJECTIVE: To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. RESULTS: We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. RESULTS: Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. CONCLUSIONS: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.
Keywords: Alzheimer Disease; Brain; Humans

Senescence Targeting Methods Impact Alzheimer's Disease Features in 3xTg Mice. - Ng, Pei Y; Zhang, Cheng; Li, Hu; Baker, Darren J (J Alzheimers Dis, 2024)
BACKGROUND: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer's disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). OBJECTIVE: To investigate the effects of senescent cell clearance in the 3xTg mouse model. METHODS: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC). RESULTS: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. CONCLUSIONS: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.
Keywords: Alzheimer Disease; Animals; Cellular Senescence; Disease Models, Animal; Mice; Mice, Transgenic; Neurodegenerative Diseases; Senotherapeutics; tau Proteins

Serial Cerebrospinal Fluid Sampling Reveals Trajectories of Potential Synaptic Biomarkers in Early Stages of Alzheimer's Disease. - Duits, Flora H; Nilsson, Johanna; Zetterberg, Henrik; Blennow, Kaj; van der Flier, Wiesje M; Teunissen, Charlotte E; Brinkmalm, Ann (J Alzheimers Dis, 2024)
BACKGROUND: Synaptic dysfunction is closely associated with cognitive function in Alzheimer's disease (AD), and is present already in an early stage of the disease. OBJECTIVE: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. METHODS: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n = 50 amyloid-β+ [A +], n = 50 A-) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4-2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. RESULTS: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] -0.27[0.12] to -0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] -0.10[0.04] to -0.15[0.05]) and SCD/MCI-A+ (St.B[SE] -0.07[0.03] to -0.12[0.03]), but not in SCD/MCI-A- (pinteraction < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] -1.75[0.58]), but not in the other groups (pinteraction < 0.05). CONCLUSIONS: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.

Sex and Sleep Disruption as Contributing Factors in Alzheimer's Disease. - Johnson, Carrie E; Duncan, Marilyn J; Murphy, M Paul (J Alzheimers Dis, 2024)
Alzheimer's disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.
Keywords: Alzheimer Disease; Animals; Cross-Sectional Studies; Female; Humans; Male; Multimorbidity; Sex Factors; Sleep; Sleep Wake Disorders

Short-Term Practice Effects on Cognitive Tests Across the Late Life Cognitive Spectrum and How They Compare to Biomarkers of Alzheimer's Disease. - Duff, Kevin; Hammers, Dustin B; Koppelmans, Vincent; King, Jace B; Hoffman, John M (J Alzheimers Dis, 2024)
BACKGROUND: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain understudied, especially with how they compare to biomarkers of AD. OBJECTIVE: The current study sought to add to this growing literature. METHODS: Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 status. RESULTS: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons. CONCLUSION: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Biomarkers; Cognition; Cognitive Dysfunction; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Practice, Psychological

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

Sleep Biomarkers for Predicting Cognitive Decline and Alzheimer's Disease: A Systematic Review of Longitudinal Studies. - Carpi, Matteo; Fernandes, Mariana; Mercuri, Nicola Biagio; Liguori, Claudio (J Alzheimers Dis, 2024)
BACKGROUND: Sleep disturbances are considered a hallmark of dementia, and strong evidence supports the association between alterations in sleep parameters and cognitive decline in patients with mild cognitive impairment and Alzheimer's disease (AD). OBJECTIVE: This systematic review aims to summarize the existing evidence on the longitudinal association between sleep parameters and cognitive decline, with the goal of identifying potential sleep biomarkers of AD-related neurodegeneration. METHODS: Literature search was conducted in PubMed, Web of Science, and Scopus databases from inception to 28 March 2023. Longitudinal studies investigating the association between baseline objectively-measured sleep parameters and cognitive decline were assessed for eligibility. RESULTS: Seventeen studies were included in the qualitative synthesis. Sleep fragmentation, reduced sleep efficiency, reduced REM sleep, increased light sleep, and sleep-disordered breathing were identified as predictors of cognitive decline. Sleep duration exhibited a U-shaped relation with subsequent neurodegeneration. Additionally, several sleep microstructural parameters were associated with cognitive decline, although inconsistencies were observed across studies. CONCLUSIONS: These findings suggest that sleep alterations hold promise as early biomarker of cognitive decline, but the current evidence is limited due to substantial methodological heterogeneity among studies. Further research is necessary to identify the most reliable sleep parameters for predicting cognitive impairment and AD, and to investigate interventions targeting sleep that can assist clinicians in the early recognition and treatment of cognitive decline. Standardized procedures for longitudinal studies evaluating sleep and cognition should be developed and the use of continuous sleep monitoring techniques, such as actigraphy or EEG headband, might be encouraged.
Keywords: Alzheimer Disease; Biomarkers; Cognition; Cognitive Dysfunction; Humans; Longitudinal Studies; Sleep

Small RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease. - Huang, Yiyao; Driedonks, Tom A P; Cheng, Lesley; Turchinovich, Andrey; Pletniková, Olga; Redding-Ochoa, Javier; Troncoso, Juan C; Hill, Andrew F; Mahairaki, Vasiliki; Zheng, Lei; Witwer, Kenneth W (J Alzheimers Dis, 2024)
BACKGROUND: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer's disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. OBJECTIVE: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. METHODS: bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. RESULTS: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. CONCLUSIONS: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Extracellular Vesicles; Female; Humans; Male; MicroRNAs; RNA, Small Untranslated; RNA, Transfer; RNA, Untranslated

Small Vessel Disease Burden Predicts Incident Dementia and Poor Functional Outcome in Independent Outpatients. - Kitagawa, Kazuo; Toi, Sono; Hosoya, Megumi; Seki, Misa; Yamagishi, Sae; Hoshino, Takao; Yoshizawa, Hiroshi (J Alzheimers Dis, 2024)
BACKGROUND: Total small vessel disease (SVD) score is used to measure the burden of SVD. OBJECTIVE: This study aimed to clarify the predictive value of total SVD score for incident dementia and functional outcomes in independent outpatients with vascular risk factors. METHODS: We derived data from a Japanese cohort in which patients underwent magnetic resonance imaging and cognitive examinations. They were followed up until March 2023. The primary outcomes was dementia. Secondary outcome was functional outcomes. We measured a modified Rankin scale (mRS) score at the last visit and defined poor functional outcomes as mRS score ≥3. RESULTS: After excluding those with a mRS score ≥2, Mini-Mental State Examination score in Japanese version < 24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, dementia occurred in 31 patients. In multivariate analysis, the score 4 group showed a significantly higher risk of incident dementia than the score 0-3 groups (adjusted hazard ratio, 6.25; 95% CI, 1.83-21.40, p = 0.003). The total SVD score was also independently related to poor functional outcome. CONCLUSIONS: The total SVD score of 4, and ≥1 could predict dementia and poor functional outcomes, respectively. Our results suggest intensive management of patients with SVD to prevent dementia and to maintain independent activities of daily living.

Social Activity and Cognitive Decline in Older Residents of Long-Term Care Facilities: A Cohort Study. - Angevaare, Milou J; Pieters, Jack A; Twisk, Jos W R; Van Hout, Hein P J (J Alzheimers Dis, 2024)
BACKGROUND: Cognitive decline is a major reason for dependence and resource use in long-term care. OBJECTIVE: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities. METHODS: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the interRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and health indicators. RESULTS: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional. CONCLUSIONS: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents.

Social support may buffer the effect of ε4 allele on cognition in older adults. - Payen, Ameanté; Bateman, James R; Dhanavanthri Muralidhara, Sneha; Sachs, Bonnie C; Cleveland, Maryjo; Yang, Mia; Lockhart, Samuel N; Craft, Suzanne; Bennett, Jeanette M (J Alzheimers Dis, 2024)
Apolipoprotein E () ε4 is a genetic risk factor for Alzheimer's disease (AD). Social support may confer protection against cognitive decline even in the presence of ε4. We examined the relationship among ε4 allele(s) carrier status, social support (overall and sub-sources), and cognition in 115 older adults (72.24 ± 8.29 years; 71.3% female). ε4 carrier status moderated social support's effect on cognition, F(1, 106) = 5.08, p = 0.03, ΔR= 0.02. Among ε4 carriers, as social support increased, cognitive functioning improved (β = 0.19, p = 0.03). This relationship was not found for ε4 non-carriers, highlighting that socio-ecological influences may interact with genetic factors to influence later-life cognition.

Socioeconomic Status and Dementia Risk Among Intensive Care Unit Survivors: Using National Health Insurance Cohort in Korea. - Park, Yu Shin; Joo, Hye Jin; Jang, Yun Seo; Jeon, Hajae; Park, Eun-Cheol; Shin, Jaeyong (J Alzheimers Dis, 2024)
BACKGROUND: In aging populations, more elderly patients are going to the intensive care unit (ICU) and surviving. However, the specific factors influencing the occurrence of post-intensive care syndrome in the elderly remain uncertain. OBJECTIVE: To investigate the association between socioeconomic status (SES) and risk of developing dementia within two years following critical care. METHODS: This study included participants from the Korean National Health Insurance Service Cohort Database who had not been diagnosed with dementia and had been hospitalized in the ICU from 2003 to 2019. Dementia was determined using specific diagnostic codes (G30, G31) and prescription of certain medications (rivastigmine, galantamine, memantine, or donepezil). SES was categorized into low (medical aid beneficiaries) and non-low (National Health Insurance) groups. Through a 1:3 propensity score matching based on sex, age, Charlson comorbidity index, and primary diagnosis, the study included 16,780 patients. We used Cox proportional hazard models to estimate adjusted hazard ratios (HR) of dementia. RESULTS: Patients with low SES were higher risk of developing dementia within 2 years after receiving critical care than those who were in non-low SES (HR: 1.23, 95% CI: 1.04-1.46). Specifically, patients with low SES and those in the high-income group exhibited the highest incidence rates of developing dementia within two years after receiving critical care, with rates of 3.61 (95% CI: 3.13-4.17) for low SES and 2.58 (95% CI: 2.20-3.03) for high income, respectively. CONCLUSIONS: After discharge from critical care, compared to the non-low SES group, the low SES group was associated with an increased risk of developing dementia.
Keywords: Aged; Dementia; Humans; Intensive Care Units; National Health Programs; Republic of Korea; Retrospective Studies; Social Class; Survivors

Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer's Disease. - Wang, Wenzhang; Zhao, Fanpeng; Torres, Sandy; Harris, Peggy L R; Wang, Xinglong; Peng, Lihua; Siedlak, Sandra L; Zhu, Xiongwei (J Alzheimers Dis, 2024)
BACKGROUND: Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer's disease following space travel. OBJECTIVE: In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer's disease mouse model. METHODS: Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiatio. RESULTS: The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. CONCLUSIONS: Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models.

The Standardized Extract of Centella asiatica and Its Fractions Exert Antioxidative and Anti-Neuroinflammatory Effects on Microglial Cells and Regulate the Nrf2/HO-1 Signaling Pathway. - Hambali, Aqilah; Jusril, Nor Atiqah; Md Hashim, Nur Fariesha; Abd Manan, Nizar; Adam, Siti Khadijah; Mehat, Muhammad Zulfadli; Adenan, Mohd Ilham; Stanslas, Johnson; Abdul Hamid, Hafizah (J Alzheimers Dis, 2024)
BACKGROUND: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer's disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown. OBJECTIVE: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells. METHODS: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting. RESULTS: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α, IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p < 0.001) by SECA and its fractions. SECA and some of its fractions can activate the Nrf2/HO-1 signaling pathway by significantly enhancing (p < 0.05) the Nrf2 and HO-1 protein expressions. CONCLUSIONS: This study suggests that the inhibitory activity of SECA and its fractions on pro-inflammatory and oxidative stress events may be the result of the activation of antioxidant defense systems. The potential of SECA and its fractions in reducing neuroinflammation and oxidative stress can be further studied as a potential therapeutic strategy for AD.
Keywords: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Centella; Heme Oxygenase-1; Lipopolysaccharides; Membrane Proteins; Mice; Microglia; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Oxidative Stress; Plant Extracts; Signal Transduction; Triterpenes

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

Targeting Caspases 3/6 and Cathepsins L/B May Decrease Laminopathy-Induced Apoptosis in Alzheimer's Disease. - Rustamzadeh, Auob; Tafakhori, Abbas; Ariaei, Armin; Heydari, Mahdi; Shah-Abadi, Mehran Ebrahimi; Seif, Farhad (J Alzheimers Dis, 2024)
BACKGROUND: Laminopathy is a pathological manifestation observed in Alzheimer's disease (AD), leading to neuronal apoptosis. OBJECTIVE: Our objective was to assess inhibitors of enzymes involved in laminopathy. METHODS: The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and ChEMBL id: 550872). RESULTS: The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. CONCLUSIONS: Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings.
Keywords: Alzheimer Disease; Apoptosis; Caspase 3; Caspase 6; Cathepsin B; Cathepsin L; Hippocampus; Humans; Lamin Type A; Laminopathies; Male; Molecular Docking Simulation

Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies. - Sigurdsson, Einar M (J Alzheimers Dis, 2024)
The tau protein undergoes pathological changes in Alzheimer's disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer's disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer's disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.
Keywords: Alzheimer Disease; Animals; Clinical Trials as Topic; Humans; Immunotherapy; tau Proteins; Tauopathies

There are dementia patients in Gaza too. - Irfan, Bilal; Abu Shammala, Abdallah; Alshaer, Nour; Nasser, Elias; Wajahath, Muaaz; Hamawy, Adam; Tahir, Mohammed; Khawaja, Haseeb; Khan, Osaama; Fikry, Karim; Kaleem, Arshad; Nasser, Mosab; et al. (J Alzheimers Dis, 2024)
This editorial highlights the devastating impact of the ongoing Israeli military assault in Gaza on dementia patients, whose fragile care systems have collapsed, leaving them vulnerable and without essential medical support. Through harrowing stories of displacement, medication shortages, and tragic deaths, the piece underscores the profound moral failure in protecting Gaza's most vulnerable, calling for urgent global action to address the humanitarian crisis and ensure dignity and healthcare for all affected individuals.
Keywords: Dementia; Humans; Middle East

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

Visual Functions Are Associated with Biomarker Changes in Alzheimer's Disease. - Memon, Ashar; Moore, Jasmine A; Kang, Chris; Ismail, Zahinoor; Forkert, Nils D (J Alzheimers Dis, 2024)
BACKGROUND: While various biomarkers of Alzheimer's disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. OBJECTIVE: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. METHODS: Data from participants (N = 1,460) in the Alzheimer's Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination (MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. RESULTS: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1-42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. CONCLUSIONS: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition.

Voluntary wheel running decreases amyloidogenic pathway and rescues cognition and mitochondrial energy metabolism in middle-aged female 3xTg-AD mouse model of Alzheimer's disease. - Dos Santos, Jonathas Rodrigo; Catalão, Carlos Henrique Rocha; Vulczak, Anderson; Azzolini, Ana Elisa Caleiro Seixas; Alberici, Luciane Carla (J Alzheimers Dis, 2024)
BACKGROUND: Evidence supports the neuroprotective effects of physical activity, either in experimental animal models or humans. However, the biological mechanisms by which physical exercise modulates dementia and Alzheimer's disease (AD) progression are still unclear. OBJECTIVE: This study investigated whether long-term (6 months) of voluntary wheel running induces neuroprotective effects in the pathogenesis of AD in middle-aged (8 months) female mice, focusing on energy metabolism. METHODS: A genetic mice model of AD (3xTg-AD) that performed wheel running presented changes in body metabolism and muscle oxidative profile, as well as restored discriminative and non-associative retention memories, evaluated by novel object recognition and open field tasks, respectively. RESULTS: In the hippocampus, these mice exhibited reduced levels of amyloidogenic AβPPβ fragment, phospho-Tau protein and phospho-Akt (activated form), without changes in phospho-AMPK (activated form). In addition, hippocampal mitochondria presented a restored respiratory function, characterized by lower coupling degree and weak contribution from complex I found in 3xTg-AD mice. CONCLUSIONS: The results demonstrated that voluntary exercise improves cognitive parameters and biochemical hallmarks of AD, modulates Akt activation and enhances mitochondrial energy metabolism in hippocampus of middle-aged 3xTg-AD female mice, thereby reinforcing the neuroprotective role of physical exercise and the involvement of mitochondria in the etiology of the AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cognition; Disease Models, Animal; Energy Metabolism; Female; Hippocampus; Mice; Mice, Transgenic; Mitochondria; Physical Conditioning, Animal; tau Proteins

A 19-Year-Old Adolescent with Probable Alzheimer's Disease. - Jia, Jianping; Zhang, Yue; Shi, Yuqing; Yin, Xuping; Wang, Shiyuan; Li, Yan; Zhao, Tan; Liu, Wenying; Zhou, Aihong; Jia, Longfei (J Alzheimers Dis, 2023)
Alzheimer's disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient's cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.
Keywords: Adolescent; Aged; Alzheimer Disease; Amyloid beta-Peptides; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography

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)

Activation of TNF Receptor 2 Improves Synaptic Plasticity and Enhances Amyloid-β Clearance in an Alzheimer's Disease Mouse Model with Humanized TNF Receptor 2. - Ortí-Casañ, Natalia; Wajant, Harald; Kuiperij, H Bea; Hooijsma, Annelien; Tromp, Leon; Poortman, Isabelle L; Tadema, Norick; de Lange, Julia H E; Verbeek, Marcel M; De Deyn, Peter P; Naudé, Petrus J W; Eisel, Ulrich L M (J Alzheimers Dis, 2023)
BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer's disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking. OBJECTIVE: The aim of this study is to investigate whether stimulation of TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model. METHODS: Transgenic amyloid-β (Aβ)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis. RESULTS: Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aβ clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity. CONCLUSION: Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Mice; Mice, Transgenic; Neuronal Plasticity; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial. - Alkon, Daniel L; Sun, Miao-Kun; Tuchman, Alan J; Thompson, Richard E (J Alzheimers Dis, 2023)
BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.
Keywords: Alzheimer Disease; Bryostatins; Cognition Disorders; Double-Blind Method; Humans; Treatment Outcome

Age-Related Association Between APOE ɛ4 and Cognitive Progression in de novo Parkinson's Disease. - Liu, Jia-Yao; Ma, Ling-Zhi; Wang, Jun; Cui, Xin-Jing; Sheng, Ze-Hu; Fu, Yan; Li, Meng; Ou, Ya-Nan; Yu, Jin-Tai; Tan, Lan; Lian, Yan (J Alzheimers Dis, 2023)
BACKGROUND: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson's disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. OBJECTIVE: To examine whether the effect of APOE ɛ4 on cognitive progression in de novo PD is age dependent. METHODS: In this study, 613 de novo PD patients were recruited from Parkinson's Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ɛ4 and cognitive changes, we added 3-way interaction of APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. RESULTS: Age significantly modified relationship between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 carriers showed steeper decline in global cognition (p = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ɛ4 and cognitive decline can be detected. CONCLUSION: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.
Keywords: Aged; Apolipoprotein E4; Cognition; Cognitive Dysfunction; Disease Progression; Genotype; Heterozygote; Humans; Parkinson Disease

An Alternative View of Familial Alzheimer's Disease Genetics. - Lardelli, Michael (J Alzheimers Dis, 2023)
Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of "pseudo-hypoxia" being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Humans; Iron; Mutation; Presenilin-1

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

Alzheimer's Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers. - Milano, Chiara; Hoxhaj, Domeniko; Del Chicca, Marta; Pascazio, Alessia; Paoli, Davide; Tommasini, Luca; Vergallo, Andrea; Pizzanelli, Chiara; Tognoni, Gloria; Nuti, Angelo; Ceravolo, Roberto; Siciliano, Gabriele; et al. (J Alzheimers Dis, 2023)
BACKGROUND: Neurosyphilis-associated cognitive and behavioral impairment- historically coined as "general paralysis of the insane"- share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer's disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging. OBJECTIVE: To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy. METHODS: We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases. RESULTS: The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD. CONCLUSION: Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression.

The Alzheimer's Disease Mitochondrial Cascade Hypothesis: A Current Overview. - Swerdlow, Russell H (J Alzheimers Dis, 2023)
Viable Alzheimer's disease (AD) hypotheses must account for its age-dependence; commonality; association with amyloid precursor protein, tau, and apolipoprotein E biology; connection with vascular, inflammation, and insulin signaling changes; and systemic features. Mitochondria and parameters influenced by mitochondria could link these diverse characteristics. Mitochondrial biology can initiate changes in pathways tied to AD and mediate the dysfunction that produces the clinical phenotype. For these reasons, conceptualizing a mitochondrial cascade hypothesis is a straightforward process and data accumulating over decades argue the validity of its principles. Alternative AD hypotheses may yet account for its mitochondria-related phenomena, but absent this happening a primary mitochondrial cascade hypothesis will continue to evolve and attract interest.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Humans; Mitochondria; Signal Transduction

Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia. - Buchman, Aron S; Leurgans, Sue E; Kim, Namhee; Agrawal, Sonal; Oveisgharan, Shahram; Zammit, Andrea R; VanderHorst, Veronique; Nag, Sukrit; Bennett, David A (J Alzheimers Dis, 2023)
BACKGROUND: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. OBJECTIVE: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. METHODS: Autopsies were obtained in decedents with cognitive testing (n = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. RESULTS: Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. CONCLUSION: Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes. - Kepp, Kasper P; Sensi, Stefano L; Johnsen, Kasper B; Barrio, Jorge R; Høilund-Carlsen, Poul F; Neve, Rachael L; Alavi, Abass; Herrup, Karl; Perry, George; Robakis, Nikolaos K; Vissel, Bryce; Espay, Alberto J (J Alzheimers Dis, 2023)
After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer's disease dementia.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Antibodies, Monoclonal; Humans; United States

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.

Apolipoprotein ɛ4-Associated Protection Against Pediatric Enteric Infections is a Survival Advantage in Pre-Industrial Populations. - Smith, Carr J; Ashford, J Wesson (J Alzheimers Dis, 2023)
Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ɛ4/ɛ4 genotype, when the ɛ3 allele mutated from the ancestral ɛ4, which elevates the risk of Alzheimer's disease. Modern humans living today predominantly carry the ɛ3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ɛ4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host's defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ɛ4 carriers, yet ɛ4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ɛ3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer's disease.

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 Between Oral Bacteria and Alzheimer's Disease: A Systematic Review and Meta-Analysis. - Liu, Sixin; Dashper, Stuart G; Zhao, Rui (J Alzheimers Dis, 2023)
BACKGROUND: Pre-clinical evidence implicates oral bacteria in the pathogenesis of Alzheimer's disease (AD), while clinical studies show diverse results. OBJECTIVE: To comprehensively assess the association between oral bacteria and AD with clinical evidence. METHODS: Studies investigating the association between oral bacteria and AD were identified through a systematic search of six databases PubMed, Embase, Cochrane Central Library, Scopus, ScienceDirect, and Web of Science. Methodological quality ratings of the included studies were performed. A best evidence synthesis was employed to integrate the results. When applicable, a meta-analysis was conducted using a random-effect model. RESULTS: Of the 16 studies included, ten investigated periodontal pathobionts and six were microbiome-wide association studies. Samples from the brain, serum, and oral cavity were tested. We found over a ten-fold and six-fold increased risk of AD when there were oral bacteria (OR = 10.68 95% CI: 4.48-25.43; p < 0.00001, I2 = 0%) and Porphyromonas gingivalis (OR = 6.84 95% CI: 2.70-17.31; p < 0.0001, I2 = 0%) respectively in the brain. While AD patients exhibited lower alpha diversity of oral microbiota than healthy controls, the findings of bacterial communities were inconsistent among studies. The best evidence synthesis suggested a moderate level of evidence for an overall association between oral bacteria and AD and for oral bacteria being a risk factor for AD. CONCLUSION: Current evidence moderately supports the association between oral bacteria and AD, while the association was strong when oral bacteria were detectable in the brain. Further evidence is needed to clarify the interrelationship between both individual species and bacterial communities and the development of AD.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Humans; Microbiota; Porphyromonas gingivalis; Risk Factors

Association of Age-Related Spontaneous Internal Jugular Vein Reflux with Cognitive Impairment and Incident Dementia. - Adachi, Utako; Toi, Sono; Hosoya, Megumi; Hoshino, Takao; Seki, Misa; Yoshizawa, Hiroshi; Tsutsumi, Yukiko; Maruyama, Kenji; Kitagawa, Kazuo (J Alzheimers Dis, 2023)
BACKGROUND: It remains unclear whether changes in the venous circulation contribute to cognitive decline. OBJECTIVE: This study aimed to clarify whether the spontaneous jugular vein reflux (JVR) is associated with cognitive impairment and incident dementia. METHODS: Patients with any evidence of cerebral vessel disease on magnetic resonance imaging (MRI) were consecutively enrolled between October 2015 to July 2019. We employed carotid duplex sonography to measure the internal jugular vein (IJV). The subjects were classified into two groups based on the degree of JVR on either side: none, mild (JVR(-) group) and moderate, severe (JVR (+) group) JVR. They underwent both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese (MoCA-J) global tests. Their cognitive status was prospectively assessed until March 2023. RESULTS: 302 patients with an MMSE score ≥24 underwent duplex sonography of the IJV. Among them, 91 had spontaneous JVR on either side. Both MMSE and MoCA-J were significantly lower in patients with JVR (+) group than in the JVR (-) group. After the adjustment for risk factors and MRI findings, intergroup differences in MoCA-J remained significant. Among the cognitive subdomains, median executive function and memory scores were significantly lower in the JVR (+) group than in the JVR (-) group. During the median 5.2-year follow-up, 11 patients with incident dementia were diagnosed. Patients with severe JVR were significantly more likely to be diagnosed with dementia (log-rank test, p = 0.031). CONCLUSIONS: Spontaneous IJV reflux especially severe JVR, was associated with global cognitive function, and potentially with incident dementia.

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 Influenza Vaccination and Dementia Risk: A Meta-Analysis of Cohort Studies. - Sun, Huimin; Liu, Min; Liu, Jue (J Alzheimers Dis, 2023)
BACKGROUND: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia. OBJECTIVE: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk. METHODS: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well. RESULTS: Of the 4,087 articles initially reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8-75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00-13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57-0.83). Subgroup analyses showed that in the study with a mean age of 75-80 years or 75%-100% males, the association was generally weakened compared with studies with a mean age of 60-75 years or 25%-50% males. The results were stable in the sensitivity analyses, and no publication bias was observed. CONCLUSION: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Dementia; Humans; Influenza, Human; Vaccination

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

Association of Sarcopenia and Its Defining Components with the Degree of Cognitive Impairment in a Memory Clinic Population. - Larsson, LE; Wang, Rui; Cederholm, Tommy; Wiggenraad, Fleur; Rydén, Marie; Hagman, Göran; Hellénius, Mai-Lis; Kivipelto, Miia; Thunborg, Charlotta (J Alzheimers Dis, 2023)
BACKGROUND: Sarcopenia and cognitive impairment are two leading causes of disabilities. OBJECTIVE: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients. METHODS: 368 patients were included (age 59.0±7.25 years, women: 58.7%), displaying three clinical phenotypes of cognitive impairments, i.e., subjective cognitive impairment (SCI, 57%), mild cognitive impairment (MCI, 26%), and Alzheimer's disease (AD, 17%). Sarcopenia was defined according to diagnostic algorithm recommended by the European Working Group on Sarcopenia in Older People. Components of sarcopenia were grip strength, bioelectrical impedance analysis, and gait speed. They were further aggregated into a score (0-3 points) by counting the numbers of limited components. Multi-nominal logistic regression was applied. RESULTS: Probable sarcopenia (i.e., reduced grip strength) was observed in 9.6% of the patients, and 3.5% were diagnosed with sarcopenia. Patients with faster gait speed showed less likelihood of MCI (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.06-0.90) and AD (OR: 0.12, 95% CI: 0.03-0.60). One or more limited sarcopenia components was associated with worse cognitive function. After adjusting for potential confounders, the association remained significant only for AD (OR 4.29, 95% CI 1.45-11.92). CONCLUSION: The results indicate a connection between the sarcopenia components and cognitive impairments. Limitations in the sarcopenia measures, especially slow walking speed, were related to poorer cognitive outcomes. More investigationsare required to further verify the causal relationship between sarcopenia and cognitive outcomes.

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 Midlife Lifestyle and Health Factors with Long-Term Changes in Blood-Based Biomarkers of Alzheimer's Disease and Neurodegeneration. - Merten, Natascha; Pinto, A Alex; Paulsen, Adam J; Chen, Yanjun; Engelman, Corinne D; Hancock, Laura M; Johnson, Sterling C; Schubert, Carla R (J Alzheimers Dis, 2023)
BACKGROUND: Pathological biomarkers of Alzheimer's disease (AD) and other dementias can change decades before clinical symptoms. Lifestyle and health factors might be relevant modifiable risk factors for dementia. Many previous studies have been focusing on associations of lifestyle and health-related factors with clinical outcomes later in life. OBJECTIVE: We aimed to determine to what extent midlife factors of lifestyle, inflammation, vascular, and metabolic health were associated with long-term changes in blood-based biomarkers of AD (amyloid beta (Aβ)) and neurodegeneration (neurofilament light chain (NfL); total tau(TTau)). METHODS: In 1,529 Beaver Dam Offspring Study (BOSS) participants (mean age 49 years, standard deviation (SD) = 9;54% were women), we applied mixed-effects models with baseline risk factors as determinants and 10-year serum biomarker change as outcomes. RESULTS: We found that education and inflammatory markers were associated with levels and/or change over time across all three markers of AD and neurodegeneration in the blood. There were baseline associations of measures of cardiovascular health with lower Aβ42/Aβ40. TTau changed little over time and was higher in individuals with diabetes. Individuals with lower risk in a number of cardiovascular and metabolic risk factors, including diabetes, hypertension, and atherosclerosis had slower accumulation of neurodegeneration over time, as determined by NfL levels. CONCLUSION: Various lifestyle and health factors, including education and inflammation, were associated with longitudinal changes of neurodegenerative and AD biomarker levels in midlife. If confirmed, these findings could have important implications for developing early lifestyle and health interventions that could potentially slow processes of neurodegeneration and AD.

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

BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease. - Yeap, Yee Jie; Kandiah, Nagaendran; Nizetic, Dean; Lim, Kah-Leong (J Alzheimers Dis, 2023)
Alzheimer's disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Humans

Best Medicine for Dementia: The Life-Long Defense of the Brain. - Andersson, Marcus J; Stone, Jonathan (J Alzheimers Dis, 2023)
This review deals with an unwelcome reality about several forms of dementia, including Alzheimer's disease- that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realit!ies of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain.
Keywords: Aging; Alzheimer Disease; Brain; Cognitive Dysfunction; Dementia; Humans

Can Traditional Board Games Prevent or Slow Down Cognitive Impairment? A Systematic Review and Meta-Analysis. - Pozzi, Federico Emanuele; Appollonio, Ildebrando; Ferrarese, Carlo; Tremolizzo, Lucio (J Alzheimers Dis, 2023)
BACKGROUND: Traditional board games can entail significant skills encompassing several cognitive functions across different domains. Therefore, they may potentially represent effective cognitive interventions in the aging population with or without Alzheimer's disease or other types of dementia. OBJECTIVE: We aimed at verifying the hypothesis that traditional board games can prevent or slow down cognitive decline, through a systematic review on traditional board games and dementia. METHODS: We searched five databases with tailored search strings. We included studies assessing the impact of board games on elderly subjects at risk of or suffering from cognitive impairment, or subjects with cognitive impairment irrespective of age. Studies where the effect of board games was not separated by cards or other games were excluded. A meta-analysis was performed for specific cognitive and non-cognitive outcomes. RESULTS: Board games improved mental function, as measured by Montreal Cognitive Assessment (p = 0.003) and Mini-Mental State Examination (p = 0.02). Ska and Go improved Trail Making Test -A, while Mahjong improved executive functions. There was no consistent effect across different games on Digit Span or Categorical Fluency. Chess improved quality of life measured with the WHO-QoL-OLD scale (p < 0.00001). Mahjong temporarily improved depressive symptoms. Go increased BDNF levels and left middle temporal gyrus and bilateral putamen metabolism. CONCLUSIONS: Traditional board games may slow global cognitive decline and improve the quality of life in elderly subjects. Different games have varying impacts on specific cognitive domains, possibly mediated by functional and biological factors.
Keywords: Aged; Alzheimer Disease; Cognition; Cognitive Dysfunction; Executive Function; Humans; Quality of Life

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.

CERAD (Consortium to Establish a Registry for Alzheimer's Disease) Neuropsychology Assessment Battery: 35 Years and Counting. - Fillenbaum, Gerda G; Mohs, Richard (J Alzheimers Dis, 2023)
BACKGROUND: In 1986, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was mandated to develop a brief neuropsychological assessment battery (CERAD-NAB) for AD, for uniform neuropsychological assessment, and information aggregation. Initially used across the National Institutes of Aging-funded Alzheimer's Disease Research Centers, it has become widely adopted wherever information is desired on cognitive status and change therein, particularly in older populations. OBJECTIVE: Our purpose is to provide information on the multiple uses of the CERAD-NAB since its inception, and possible further developments. METHODS: Since searching on "CERAD neuropsychological assessment battery" or similar terms missed important information, "CERAD" alone was entered into PubMed and SCOPUS, and CERAD-NAB use identified from the resulting studies. Use was sorted into major categories, e.g., psychometric information, norms, dementia/differential dementia diagnosis, epidemiology, intervention evaluation, genetics, etc., also translations, country of use, and alternative data gathering approaches. RESULTS: CERAD-NAB is available in ∼20 languages. In addition to its initial purpose assessing AD severity, CERAD-NAB can identify mild cognitive impairment, facilitate differential dementia diagnosis, determine cognitive effects of naturally occurring and experimental interventions (e.g., air pollution, selenium in soil, exercise), has helped to clarify cognition/brain physiology-neuroanatomy, and assess cognitive status in dementia-risk conditions. Surveys of primary and tertiary care patients, and of population-based samples in multiple countries have provided information on prevalent and incident dementia, and cross-sectional and longitudinal norms for ages 35-100 years. CONCLUSION: CERAD-NAB has fulfilled its original mandate, while its uses have expanded, keeping up with advances in the area of dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cross-Sectional Studies; Humans; Neuropsychological Tests; Neuropsychology; Psychometrics; Registries