Volume 79, Number 4, IN PRESS

Review
Jack C. de la Torre
Deciphering Alzheimer’s Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR
Abstract: This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor’s active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH.

Review
Eloi Magnin
Neurodevelopmental and Neurodegenerative Similarities and Interactions: A Point of View About Lifelong Neurocognitive Trajectories
Abstract: Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with similarities and frequent complex interactions with each other. Taking these aspects into account can provide a new point of view on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments is challenging but might improve diagnostic accuracy and physiopathological understanding. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized precision cognitive medicine.

Review
Lei Huang, Yang Zhang, Yongwei Wang, Yajia Lan
Relationship Between Chronic Noise Exposure, Cognitive Impairment, and Degenerative Dementia: Update on the Experimental and Epidemiological Evidence and Prospects for Further Research
Abstract: Degenerative dementia, of which Alzheimer’s disease is the most common form, is characterized by the gradual deterioration of cognitive function. The events that trigger and promote degenerative dementia are not clear, and treatment options are limited. Experimental and epidemiological studies have revealed chronic noise exposure (CNE) as a potential risk factor for cognitive impairment and degenerative dementia. Experimental studies have indicated that long-term exposure to noise might accelerate cognitive dysfunction, amyloid-β deposition, and tau hyperphosphorylation in different brain regions such as the hippocampus and cortex. Epidemiological studies are increasingly examining the possible association between external noise exposure and dementia. In this review, we sought to construct a comprehensive summary of the relationship between CNE, cognitive dysfunction, and degenerative dementia. We also present the limitations of existing evidence as a guide regarding important prospects for future research.

Review
Kejing Lao*, Ruisan Zhang*, Jing Luan, Yuelin Zhang, Xingchun Gou *These authors contributed equally to this work
Therapeutic Strategies Targeting Amyloid-β Receptors and Transporters in Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors and transporters to provide a molecular basis for future rational design of anti-AD agents.

Review
Vedad Delic, Whitney A. Ratliff, Bruce A. Citron
Sleep Deprivation, a Link Between Post-Traumatic Stress Disorder and Alzheimer’s Disease
Abstract: An estimated 5 million Americans are living with Alzheimer’s disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of inadequate sleep have been shown to cause an increase in amyloid-β and tau proteins, both well-established contributors to AD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology.

Short Communication
Andrée-Ann Baril, Alexa S. Beiser, Susan Redline, Emer R. McGrath, Daniel J. Gottlieb, Hugo Aparicio, Sudha Seshadri, Jayandra J. Himali*, Matthew P. Pase* (Handling Associate Editor: Shireen Sindi) *These authors contributed equally.
Interleukin-6 Interacts with Sleep Apnea Severity when Predicting Incident Alzheimer’s Disease Dementia
Abstract: Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer’s type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Rachel Underlien Kristensen, Christina Jensen-Dahm, Christiane Gasse, Gunhild Waldemar
Declining Use of Potentially Inappropriate Medication in People with Dementia from 2000 to 2015: A Repeated Cross-Sectional Nationwide Register-Based Study
Abstract: Background: Studies have shown declining use of potentially inappropriate medication (PIM), medication where risks associated with use outweigh potential benefits in older people. However, the trend in people with dementia remains unknown. Objective: To test the hypothesis that the use of PIM has decreased in people with dementia in line with the declining use in the general older population. Methods: Repeated cross-sectional register-based study of the entire Danish population aged ≥65 years (2000: N=802,106; 2015: N=1,056,476). PIM was identified using the Danish “Red-yellow-green list”. Changes in the use of PIM were examined by calculating the annual prevalence of filling prescriptions for at least one PIM in older people with and without dementia. Characteristics of the study population were examined annually including comorbidity. Results: From 2000 to 2015, the prevalence of PIM use decreased from 54.7% to 43.5% in people with dementia and from 39.5% to 28.8% in people without dementia; the decrease was significant across all age groups and remained so in a sensitivity analysis where antipsychotics were removed. During the same period, comorbidity scores increased in people with and without dementia. Conclusion: The declining use of PIM in people with dementia from 2000 to 2015 parallels the trend in the general older population. The use of PIM decreased despite increasing levels of comorbidity and was not solely attributable to the decreasing use of antipsychotics in people with dementia. However, PIM use remained more widespread in people with dementia who may be more vulnerable to the risks associated with PIM.

Yang Hyun Lee*, Seun Jeon*, Han Soo Yoo, Seok Jong Chung, Jin Ho Jung, Kyoungwon Baik, Young H. Sohn, Phil Hyu Lee, Mijin Yun, Alan C. Evans, Byoung Seok Ye *These authors contributed equally to this work.
Effect of Alzheimer’s Disease and Lewy Body Disease on Metabolic Changes
Abstract: Background: The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer’s disease (AD) and Lewy body disease (LBD). Objectives: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. Methods: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Results: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Conclusions: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases.

Sindana D. Ilango, Kevin Gonzalez, Linda Gallo, Matthew A. Allison, Jianwen Cai, Carmen R. Isasi, H. Dean Hosgood, Priscilla M. Vasquez, Donglin Zeng, Marion Mortamais, Hector Gonzalez, Tarik Benmarhnia
Long-Term Exposure to Ambient Air Pollution and Cognitive Function Among Hispanic/Latino Adults in San Diego, California
Abstract: Background: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. Objective: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. Methods: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and executive function (n=2,089). Air pollution (PM2.5 and O3) before study baseline was assigned to participants’ zip code. Logistic and linear regression were used to estimate the association of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. Results: We found that for every 10 µg/m3 increase in PM2.5, verbal fluency worsened (β: -0.21 [95% CI: -0.68, 0.25]). For every 10 ppb increase in O3, verbal fluency and executive function worsened (β: -0.19 [95% CI: -0.34, -0.03]; β: -0.01 [95% CI: -0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. Conclusion: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults.

Benoît Jobin, Rayane Zahal, Eve-Line Bussières, Johannes Frasnelli, Benjamin Boller (Handling Associate Editor: Kerryn Pike)
Olfactory Identification in Subjective Cognitive Decline: A Meta-Analysis
Abstract: Background: Recently, subjective cognitive decline (SCD) has been considered to be one of the first signs of Alzheimer’s disease (AD). Since this potential early marker is sensitive but not specific to AD, combining it with other markers could ensure higher accuracy when predicting which persons with SCD will convert to AD. Since olfactory dysfunction is observable in both AD and mild cognitive impairment (MCI), it is a promising marker that could help improve the early diagnosis of AD. Objective: The aim of this meta-analysis was to verify whether the presence of SCD is associated with a decrease in olfactory identification ability. Methods: We collected articles from the following databases: PsychNet, PubMed, Ebsco, and ProQuest using the keywords: “SCD’’, “subjective cognitive decline”, “subjective cognitive impairment”, “subjective memory impairment”, “subjective memory decline”, “cognitive complaints’’, “memory complaints”, “cognitive concerns’’, “memory concerns’’, “olfac*” and “smell”. We included articles according to the following criteria: 1) participants aged 50 and over; 2) presence of an SCD group or a conceptual equivalent; 3) presence of a healthy control group with the same age range; and 4) assessment of olfactory identification ability. Results: Five studies met the inclusion criteria. Small and homogeneous effects were observed for olfactory identification alteration in individuals with SCD relative to controls (g = -0.16, 95% CI [-0.46, 0.14]). Conclusion: Despite the low number of studies included, the findings suggest that odor identification is slightly altered in SCD compared to healthy older adults. This alteration in individuals with SCD could be an early marker of AD.

Alberto Castagna, Andrea Fabbo, Ciro Manzo, Roberto Lacava, Carmen Ruberto, Giovanni Ruotolo (Handling Associate Editor: Patrizia Mecocci)
A Retrospective Study on the Benefits of Combined Citicoline, Memantine, and Acetylcholinesterase Inhibitor Treatments in Older Patients Affected with Alzheimer’s Disease
Abstract: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11% of men, mean age 76,81±4.93 years): 48.8% treated with memantine and donepezil; 48.2% with memantine and rivastigmine; 2.9% with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p=0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p=0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months.

Alejandra Martínez-Maldonado, Miguel Ángel Ontiveros-Torres, Charles R. Harrington, José Francisco Montiel-Sosa, Raúl García-Tapia Prandiz, Patricia Bocanegra-López, Andrew Michael Sorsby-Vargas, Marely Bravo-Muñoz, Benjamín Florán-Garduño, Ignacio Villanueva-Fierro, George Perry, Linda Garcés-Ramírez, Fidel de la Cruz, Sandra Martínez-Robles, Mar Pacheco-Herrero, José Luna-Muñoz (Handling Editor: Jesús Ávila)
Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration
Abstract: Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with the repeated microtubule-binding domains of three (3R) or four (4R) repeats. Under normal conditions, the 4R:3R ratio is 1:1. In PSP, the 4R isoform is predominantly expressed. The lesions in PSP brains are phosphorylated tau aggregates in both neurons and glial cells. These neurodegenerative diseases with abnormal tau inclusions are called tauopathies, including Alzheimer’s disease (AD). AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. Objective: Our objective was to evaluate and compare the pathological tau processing in PSP and AD. Methods: Double and triple immunofluorescence with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Truncated tau at Glu391 and Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR and the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was abundantly evidenced in PSP as in AD. The presence of eNFTs in glial cells and neuronal bodies suggest that other truncated tau species different from those observed in AD could be present in PSP. Additional studies on truncated tau within PSP lesions could improve understanding of tau’s pathological processing and help identify a discriminatory biomarker for AD and PSP.

Mithilesh Prakash, Mahmoud Abdelaziz, Linda Zhang, Bryan A. Strange, Jussi Tohka, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Malek Adjouadi)
Quantitative Longitudinal Predictions of Alzheimer’s Disease by Multi-Modal Predictive Learning
Abstract: Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and 36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months = 4.1, 4.5, and 5.0, ρ12, 24 & 36 months = 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months = 3.5, 3.7, and 4.6, ρ12, 24 & 36 months = 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials.

Rasha H. Mehder, Brian M. Bennett, R. David Andrew (Handling Associate Editor: Sergio Ferreira)
Age-Related Neuronal Deterioration Specifically Within the Dorsal CA1 Region of the Hippocampus in a Mouse Model of Late Onset Alzheimer's Disease
Abstract:
Background: Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective: We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods: Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results: The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion: This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory.

Yen Ying Lim, Matthew P. Pase, Rachel F. Buckley, Nawaf Yassi, Lisa Bransby, Christopher Fowler, Simon M. Laws, Colin L. Masters, Paul Maruff
Visual Memory Deficits in Middle-Aged APOE ε4 Homozygotes Detected Using Unsupervised Cognitive Assessments
Abstract: Background: The apolipoprotein E (APOE) ε4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ε4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ε4 heterozygotes; 50 ε4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ε4 heterozygotes; 31 ε4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ε4 homozygotes compared with ε4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ε4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ε4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ε4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ε4 homozygosity increases with older age. APOE ε4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

Zhouyuan Peng, Hiroyuki Nishimoto, Ayae Kinoshita (Handling Associate Editor: Shun Shimohama)
Driving Performance and Its Correlation with Neuropsychological Tests in Senior Drivers with Cognitive Impairment in Japan
Abstract: Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological test that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ = -0.707, p < 0.01), BDT (ρ = -0.560, p < 0.05), and ADAS (ρ = 0.758, p < 0.01), “Forgetting to use turn signals” with the TMT-B score (ρ = 0.608, p < 0.05), “Centerline crossings” with the scores of MMSE (ρ = -0.582, p < 0.05) and ADAS (ρ = 0.538, p < 0.05), and “Going the wrong way” was correlated with the score of CDT (ρ = -0.624, p < 0.01). Conclusion: Different neuropsychological factors serve as predictors of different specific driving maneuvers segmented from driving performance.

Francisca S. Rodriguez, Alexander Pabst, Kathrin Heser, Luca Kleineidam, Andre Hajek, Marion Eisele, Susanne Röhr, Margrit Löbner, Birgitt Wiese, Matthias C. Angermeyer, Wolfgang Maier, Martin Scherer, Michael Wagner, Hans-Helmut König, Steffi G. Riedel-Heller
Disorientation in Time and Place in Old Age: Longitudinal Evidence from Three Old Age Cohorts in Germany (AgeDifferent.de Platform)
Abstract: Background: Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer’s disease and related dementias. Objectives: The aim of this study was to investigate the prevalence of disorientation in older age in association with the level of cognitive status, personal characteristics, and life events. Methods: Three longitudinal population-based cohort studies on cognitive health of elderly adults were harmonized (LEILA 75+, AgeCoDe/AgeQualiDe, AgeMooDe). Participants who completed a baseline and at least one follow-up assessment of cognitive functioning and who did not have stroke, Parkinson’s disease, atherosclerosis, kidney disease, and/or alcoholism were included in the analysis (n=2135, 72.6% female, mean age 80.2 years). Data was collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant’s general practitioner. Results: Making three errors in the MMSE other than in the questions on orientation (MMSEwo) came with a probability of 7.8% for disorientation, making ten errors with a probability of 88.9%. A lower MMSEwo score (HR 0.75, CI 95 0.71-0.79, p<0.001), older age (HR 1.11, CI 95 1.08-1.14, p<0.001), and living in a nursing home (HR 1.64, CI 95 1.02-2.64, p=0.042) were associated with incident disorientation. Impairments in walking (OR 2.41, CI 95 1.16-4.99, p=0.018) were associated with a greater probability for prevalent disorientation. None of the life events were significant. Conclusion: Our findings suggest that disorientation is primarily associated with cognitive status. Regular walking activities might possibly reduce the risk for disorientation but further research is necessary.

Johan Frederik Håkonsen Arendt, Erzsébet Horváth-Puhó, Henrik Toft Sørensen, Ebba Nexø, Lars Pedersen, Anne Gulbech Ording, Victor W. Henderson (Handling Associate Editor: William Grant)
Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia
Abstract: Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia. Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. Conclusion: We found no association between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

Sen Li, Yushan Yi, Ke Cui, Yanqiu Zhang, Yange Chen, Dou Han, Ling Sun, Xiaohui Zhang, Fei Chen, Yixin Zhang, Yufeng Yang (Handling Associate Editor: Ling-Qiang Zhu)
A Single-Chain Variable Fragment Antibody Inhibits Aggregation of Phosphorylated Tau and Ameliorates Tau Toxicity in vitro and in vivo
Abstract: Background: Alzheimer’s disease (AD) is a common cause of dementia among elderly people. Hyperphosphorylation and aggregation of tau correlates with the clinical progression of AD; therefore, therapies targeting the aggregation of tau may have potential applications for anti-AD drug development. Several inhibitors of tau aggregation, including small molecules and antibodies, have been found to decrease the aggregation of tau and the corresponding pathology. Objective: To screen one kind of single-chain variable fragment (scFv) antibody which could inhibit the aggregation of tau and ameliorate its cytotoxicity. Methods/Results: Using phosphorylated tau (pTau) as an antigen, we obtained a scFv antibody via the screening of a high-capacity phage antibody library. Biochemical analysis revealed that this scFv antibody (scFv T1) had a strong ability to inhibit pTau aggregation both in dilute solutions and under conditions of macromolecular crowding. ScFv T1 could also depolymerize preformed pTau aggregates in vitro. Furthermore, scFv T1 was found to be able to inhibit the cytotoxicity of extracellular pTau aggregates and ameliorate tau-mediated toxicity when coexpressed with a hTauR406W mutant in the eye of transgenic Drosophila flies. Conclusion: This scFv T1 antibody may be a potential new therapeutic agent against AD. Our methods can be used to develop novel strategies against protein aggregation for the treatment of neurodegenerative diseases.

Jin-Hyuck Park, Sang Ah Lee
The Fragility of Temporal Memory in Alzheimer’s Disease
Abstract: Background: Although episodic memory impairment is one of the hallmarks of Alzheimer’s disease (AD), the relative decline in the components of episodic memory (What, Where, and When) and the effects of cognitive training on each of them are still unknown. Objective: We aimed to independently assess the impairment in each component of episodic memory in early to moderate AD and address whether it can be enhanced through active, spatiotemporal episodic training. Methods: A non-verbal scene-based episodic memory task was developed to assess the ability to remember What, Where, and When information. Experiment 1 tested whether this task can differentiate AD subjects (N = 16) from healthy controls (N = 16). In Experiment 2, 13 AD subjects underwent 16 training sessions, followed by a re-administration of the scene-based memory task. Experiment 3 tested 42 healthy older adults and 51 younger adults on the same task to investigate the effects of normal aging. Results: Of the three components, When memory had the highest predictive power in distinguishing AD from normal aging. Following training of AD subjects, only Where memory improved. Only What memory revealed a significant decline in healthy subjects from 65-85 years of age. Conclusion: These findings shed new light on the importance of the temporal component of episodic memory as a behavioral marker of AD. The selective improvement of spatial but not temporal memory through training further demonstrates the fragility of temporal memory even in early AD. Neuroscientific research is needed to distinguish whether the Where component was enhanced by improvements in hippocampal spatial representation or by other compensatory mechanisms.

Ruozhen Wu*, Jianlan Gu*, Dingwei Zhou, Yunn Chyn Tung, Nana Jin, Dandan Chu, Wen Hu, Jerzy Wegiel, Cheng-Xin Gong, Khalid Iqbal, Fei Liu *These authors contributed equally to this work.
Seeding-Competent Tau in Gray Matter Versus White Matter of Alzheimer’s Disease Brain
Abstract: Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity was quantitatively assessed by measuring RIPA-buffer–insoluble tau in HEK-293FT/Tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151-391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter.

Ana Sofia Costa, João Pinho, Domantė Kučikienė, Arno Reich, Jörg B. Schulz, Kathrin Reetz (Handling Associate Editor: Jun Ni)
Cerebral Amyloid Angiopathy in Amyloid-Positive Patients from a Memory Clinic Cohort
Abstract: Background: The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is frequent and relevant for patients with cognitive impairment. Objective: To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Methods: Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white matter hyperintensities, perivascular spaces) characteristics. Results: Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1-42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95%CI] = 0.90-0.98, p=0.003), and Aβ1-40 (aOR = 0.98, 95%CI=0.97-0.99 p=0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95%CI=1.21-11.15, p=0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. Conclusion: The presence of probable CAA in Aβ positive patients was associated with lower Aβ1-42 and Aβ1-40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window.

Hany I. Hassanin, Heba M. Tawfik, Stelios Zygouris, Marianna Tsatali, Hala S. Sweed, Magda Tsolaki
Setting Up a Cognitive Training Service for Egyptian Older Adults
Abstract: Background: With greying of nations, dementia becomes a public health priority. The rising dementia prevalence escalates both health care expenses and burden, placing the entire healthcare system and caregivers under huge stress. Cognition-oriented interventions have been shown to enhance the overall cognitive performance among healthy and cognitively impaired older adults. Objective: This article is assumed to be a steppingstone for the introduction and establishment of cognition- oriented interventions in Egypt. In addition, it aims to offer provisional guidance for health care providers in Arab speaking countries in a stepwise approach in order to establish cognition-oriented intervention services and help them to evaluate and monitor their efficacy. Methods: A consortium of Egyptian and Greek specialists developed a protocol for the operations of the Ain Shams Cognitive Training Lab and the provision of cognition-oriented interventions. This protocol is based on a previous successful protocol that has been implemented in Greece for more than 10 years and is co-designed to fit the needs of older adults in Arabic speaking countries. Results: The types of services offered, their objectives, recruitment of participants, delivery of interventions, measurement of outcomes and privacy policy are all outlined in the policy. Conclusion: Establishing the appropriate framework in which cognitive training strategies can be adapted and implemented in Arabic population, constitutes an inevitable achievement in healthy ageing and can be also assumed as a dementia prevention strategy. Moreover, setting up the first cognitive laboratory in Egypt older adults, can be a model of good practice across the Arabic countries.

Jens Bohlken, Steffi Riedel-Heller, Gilles Steininger, Karel Kostev, Bernhard Michalowsky
Trends in Dementia and Mild Cognitive Impairment Prevalence and Incidence in German General and Specialist Practices Between 2015 and 2019
Abstract: Background: The number of patients with dementia is forecast to grow continuously. However, there are indications that the incidence and prevalence is falling in high-income countries. Objective: To examine whether any effects of declining incidence and prevalence rates of dementia and mild cognitive impairment (MCI) were evident in Germany between 2015 and 2019. Methods: The analysis was based on 797 general and 132 specialists (neurological/psychiatric) practices and included 10.1 million patients aged 18 years and older who visited between January 2014 and December 2019 one of the practitioners. The prevalence and incidence of dementia and MCI were demonstrated descriptively. Results: Between 2015 and 2019, the prevalence (incidence) of dementia decreased from 2.18% (0.44%) in 2015 to 2.07% (0.35%) in 2019. A relatively large decrease in the prevalence (incidence) of dementia was observed in patients aged 80 and older, at -1.47% (-0.62%), compared to younger patients, at -0.40% (-0.18%). By contrast, the prevalence and incidence of MCI have remained constant over the years (0.19% to 0.22% and 0.06%, respectively). Overall, the number of patients diagnosed with dementia decreased slightly by 1% while the number of patients diagnosed with MCI increased by 17%, which is caused by continued demographic changes. Conclusion: Our results confirmed the reduction in the prevalence and incidence of dementia and revealed a decrease in the number of patients with dementia despite continued demographic changes. Future studies are warranted to determine whether the results are caused by changing risk and lifestyle factors or changes in medical diagnosis and treatment behavior of the practitioners.

Fan Zhang, Melissa Petersen, Leigh Johnson, James Hall, Sid E. O’Bryant
Recursive Support Vector Machine Biomarker Selection for Alzheimer's Disease
Abstract: Background: There is a need for more reliable diagnostic tools for the early detection of Alzheimer’s disease (AD). This can be a challenge due to a number of factors and logistics making machine learning a viable option. Objective: In this paper, we present on a Support Vector Machine Leave-One-Out Recursive Feature Elimination and Cross Validation (SVM-RFE-LOO) algorithm for use in the early detection of AD and show how the SVM-RFE-LOO method can be used for both classification and prediction of AD. Methods: Data were analyzed on n=300 participants (n=150 AD; n=150 cognitively normal controls). Serum samples were assayed via a multi-plex biomarker assay platform using electrochemiluminescence (ECL). Results: The SVM-RFE-LOO method reduced the number of features in the model from 21 to 16 biomarkers and achieved an area under the curve (AUC) of 0.980 with a sensitivity of 94.0% and a specificity of 93.3%. When the classification and prediction performance of SVM-RFE-LOO was compared to that of SVM and SVM-RFE, we found similar performance across the models; however, the SVM-RFE-LOO method utilized fewer markers. Conclusion: We found that 1) the SVM-RFE-LOO is suitable for analyzing noisy high-throughput proteomic data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance. Our recursive feature elimination model can serve as a general model for biomarker discovery in other diseases.

Tetsuo Hayashi, Shotaro Shimonaka, Montasir Elahi, Shin-Ei Matsumoto, Koichi Ishiguro, Masashi Takanashi, Nobutaka Hattori, Yumiko Motoi
Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer’s Disease Brain Extract in Mouse Brains
Abstract: Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

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

Shlomo Sragovich, Michael Gershovits, Jacqueline C.K. Lam, Victor O.K. Li, Illana Gozes
Putative Blood Somatic Mutations in Post-Traumatic Stress Disorder-Symptomatic Soldiers: High Impact of Cytoskeletal and Inflammatory Proteins
Abstract: Background: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer’s disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. Objective: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. Methods: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, PTSD) was performed. Results: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. Conclusion: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design.

Elsa Lehingue, Julien Gueniat, Sandra Jourdaa, Jean Benoît Hardouin, Amandine Pallardy, Hélène Courtemanche, Laëtitia Rocher, Frédérique Etcharry-Bouyx, Sophie Auriacombe, Hélène Mollion, Maité Formaglio, Olivier Rouaud, Cédric Bretonnière, Catherine Thomas Antérion, Claire Boutoleau-Bretonnière (Handling Associate Editor: Michael Hornberger)
Improving the Diagnosis of the Frontal Variant of Alzheimer’s Disease with the DAPHNE Scale
Abstract: Background: The frontal variant of Alzheimer’s disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. Objective: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. Methods: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. Results: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. Conclusion: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

Paraskevi Iliadou, Ioannis Paliokas, Stelios Zygouris, Eftychia Lazarou, Konstantinos Votis, Dimitrios Tzovaras, Magdalini Tsolaki
A Comparison of Traditional and Serious Game-Based Digital Markers of Cognition in Older Adults with Mild Cognitive Impairment and Healthy Controls
Abstract: Background: Electroencephalography (EEG) has been used to assess brain activity while users are playing an immersive serious game. Objective: To assess differences in brain activation as measured with a non-intrusive wearable EEG device, differences in game performance and correlations between EEG power, game performance and global cognition, between cognitively impaired and non-impaired older adults, during the administration of a novel self-administered serious game-based test, the Virtual Supermarket Test (VST). Methods: 43 older adults with subjective cognitive decline (SCD) and 33 older adults with mild cognitive impairment (MCI) were recruited from day centers for cognitive disorders. Global cognition was assessed with the Montreal Cognitive Assessment (MoCA). Brain activity was measured with a non-intrusive wearable EEG device in a resting state condition and while they were administered the VST. Results: During resting state condition, the MCI group showed increased alpha, beta, delta, and theta band power compared to the SCD group. During the administration of the VST, the MCI group showed increased beta and theta band power compared to the SCD group. Regarding game performance, alpha, beta, delta, and theta rhythms correlated with average duration, while delta rhythm was positively correlated with mean errors. MoCA correlated with alpha, beta, delta, and theta rhythms and with average game duration and mean game errors indicating that elevated EEG rhythms in MCI may be associated with an overall cognitive decline. Conclusion: VST performance can be used as a digital biomarker. Cheap commercially available wearable EEG devices can be used for obtaining brain activity biomarkers.

Rachel M. Shaffer, Ge Li, Sara D. Adar, C. Dirk Keene, Caitlin S. Latimer, Paul K. Crane, Eric B. Larson, Joel D. Kaufman, Marco Carone, Lianne Sheppard
Fine Particulate Matter and Markers of Alzheimer’s Disease Neuropathology at Autopsy in a Community-Based Cohort
Abstract: Background: Evidence links fine particulate matter (PM2.5) to Alzheimer’s disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). Methods: We used autopsy specimens (N=832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. Results: 10-year average PM2.5 from death across the autopsy cohort was 8.2 (1.9) µg/m3. Average age at death was 89 (±7) years. Each 1 µg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19). There was no association with Braak stage (OR: 0.99 (0.64, 1.47). Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.

Yifei Lu, James R. Pike, Elizabeth Selvin, Thomas Mosley, Priya Palta, A. Richey Sharrett, Alvin Thomas, Laura Loehr, A. Sidney Barritt, Ron C. Hoogeveen, Gerardo Heiss
Low Liver Enzymes and Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study
Abstract: Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996-1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values < 10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08-1.65). The corresponding HR was 1.22 (0.99-1.51) for AST. Conclusion: Plasma aminotransferases < 10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia.

Xueshen Qian*, Shuang Zhang*, Lian Duan, Fengchun Yang, Kun Zhang, Fuhua Yan, Song Ge *These authors contributed equally to this work.
Periodontitis Deteriorates Cognitive Function and Impairs Neurons and Glia in a Mouse Model of Alzheimer’s Disease
Abstract: Background: Although periodontitis is reportedly associated with increased cognitive decline in Alzheimer’s disease (AD), the mechanisms underlying this process remain unknown. Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) is an endotoxin associated with periodontal disease. Objective: We investigated the effect of periodontitis on learning capacity and memory of amyloid-β protein precursor (AβPP)/presenilin (PS1) transgenic mice, as well as mechanisms underlying these effects. Methods: Mice were randomly assigned to three groups: AβPP/PS1 (control); P.g-LPS Injection; and P.g-LPS Injection+Ligation. The periodontal tissue of P.g-LPS injection group was injected with P.g-LPS three times per week for 8 weeks, while mice of the P.g-LPS + ligation group were injected with P.g-LPS, and then subjected to ligation of the gingival sulcus of the maxillary second molar. Results: Expression levels of gingival proinflammatory cytokines as well as alveolar bone resorption of P.g-LPS-injected and ligatured mice were increased compared to those of control mice. Mice in the P.g-LPS Injection+Ligation group displayed cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased amyloid-β (Aβ) levels, was more pronounced relative to the control group. Induction of periodontitis concurrently increased the expression of cyclooxygenase-2, inducible nitric oxide synthase, AβPP and beta-secretase 1, and decreased that of A disintegrin and metalloproteinase domain-containing protein 10. Conclusion: These findings indicated that periodontitis exacerbated learning and memory impairment in AβPP/PS1 mice and augmented Aβ and neuroinflammatory responses. Our study provides a theoretical basis for risk prediction and early intervention of AD and periodontitis.

Maria Ly*, Cyrus A. Raji*, Gary Z. Yu, Qing Wang, Yong Wang, Suzanne E. Schindler, Hongyu An, Amjad Samara, Sarah A. Eisenstein, Tamara Hershey, Gordon Smith, Samuel Klein, Jingxia Liu, Chengjie Xiong, Beau M. Ances, John C. Morris, Tammie L.S. Benzinger *These authors contributed equally to this work.
Obesity and White Matter Neuroinflammation Related Edema in Alzheimer's Disease Dementia Biomarker Negative Cognitively Normal Individuals
Abstract: Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI<25, N=62) or overweight and obese (BMI≥25, N=42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI<25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR corrected for multiple comparisons to alpha=0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, cingulate gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly.

Madhumathi Gnanaprakash, Agnieszka Staniszewski, Hong Zhang, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls (Handling Associate Editor: Domenico Pratico)
Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice
Abstract: Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.