Volume 86, Number 1, 2022

Pages 1-3

Jamie Talan
Obituary for John Q. Trojanowski, leading Alzheimer’s Disease Researcher

Pages 5-19

Kaitlyn E. Stepler, Taneisha R. Gillyard, Calla B. Reed, Tyra M. Avery, Jamaine S. Davis, Renã A.S. Robinson
ABCA7, a Genetic Risk Factor Associated with Alzheimer’s Disease Risk in African Americans
Abstract: African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ε4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.

Pages 21-42

Mohammad Nami, Robert Thatcher, Nasser Kashou, Dahabada Lopes, Maria Lobo, Joe F. Bolanos, Kevin Morris, Melody Sadri, Teshia Bustos, Gilberto E. Sanchez, Alena Mohd-Yusof, John Fiallos, Justin Dye, Xiaofan Guo, Nicholas Peatfield, Milena Asiryan, Alero Mayuku-Dore, Solventa Krakauskaite, Ernesto Palmero Soler, Steven C. Cramer, Walter G. Besio, Antal Berenyi, Manjari Tripathi, David Hagedorn, Morgan Ingemanson, Marinela Gombosev, Mark Liker, Yousef Salimpour, Martin Mortazavi, Eric Braverman, Leslie S. Prichep, Deepak Chopra, Dawn S. Eliashiv, Robert Hariri, Ambooj Tiwari, Ken Green, Jason Cormier, Namath Hussain, Nevzat Tarhan, Daniel Sipple, Michael Roy, John S. Yu, Aaron Filler, Mike Chen, Chris Wheeler, J. Wesson Ashford, Kenneth Blum, Deborah Zelinsky, Vicky Yamamoto, Babak Kateb
A Proposed Brain-, Spine-, and Mental- Health Screening Methodology (NEUROSCREEN) for Healthcare Systems: Position of the Society for Brain Mapping and Therapeutics
Abstract: The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales.

Pages 43-48
Short Communication
Michelle C. Johansen, Wendy Wang, Michael J. Zhang, Alvaro Alonso, Dean F. Wong, Rebecca F. Gottesman, Lin Y. Chen
Associations Between Atrial Arrhythmias and Brain Amyloid Deposition: The ARIC-PET Study
Abstract: The aim of this study is to determine if there is an association between atrial arrhythmias and brain amyloid-β (Aβ), measured on florbetapir (FBP) PET. 346 nondemented participants from the Atherosclerosis Risk in Communities study underwent FBP-PET, 185 also wore Zio® XT Patch. The associations between global cortical Aβ (>1.2 standardized uptake value ratio) and history of atrial fibrillation, zio-defined atrial tachycardia and premature atrial contractions, each, were evaluated. Among nondemented community-dwelling older adults, we did not find an association between atrial arrhythmias and Aβ. Other brain pathology may underlie the association described between atrial arrhythmias and cognition.

Pages 49-52

Timothy Daly, Ignacio Mastroleo, Vincent Henry, Mathieu Bourdenx
An Argument for Simple Tests of Treatment of Alzheimer’s Disease
Abstract: Two potential disease-modifying approaches for dementia are being vigorously tested: the early targeting of the neuropathology of Alzheimer’s disease (AD) and multi-domain lifestyle interventions to promote resilience to neuropathology. We apply the “web of information” model of clinical translation to both approaches to argue firstly that tests of treatments aiming to achieve clinically meaningful outcomes should remain simple, and secondly, that building clinically-meaningful treatments should be kept separate from public health policy which means promoting wide-reaching action against risk factors now with available information.

Pages 53-65
Alexander Ivan B. Posis, Wassim Tarraf, Kevin A. Gonzalez, Jose A. Soria-Lopez, Gabriel C. Léger, Ariana M. Stickel, Martha L. Daviglus, Melissa Lamar, Donglin Zeng, Hector M. González
Anticholinergic Drug Burden and Neurocognitive Performance in the Study of Latinos-Investigation of Neurocognitive Aging
Abstract: Background: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. Objective: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. Methods: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. Results: Anticholinergic use was associated with lower cognitive global cognition (β = –0.21; 95%CI [–0.36; –0.05]), learning (β = –0.27; 95%CI [–0.47; –0.07]), memory (β = –0.22; 95%CI [–0.41; –0.03]), and executive functioning (β = –0.22; 95%CI [–0.40; –0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: –0.28 [95% CI: –0.55, –0.01]; β: –0.28 [95% CI: –0.55, –0.01]; β: –0.25, [95% CI –0.47, –0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3=3.59, F3=2.84, F3=3.88, respectively). Conclusion: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

Pages 67-81
Ruijie Liu*, Chenhao Gao*, Junkui Shang, Ruihua Sun, Wenjing Wang, Wei Li, Dandan Gao, Xuejing Huo, Yingying Shi, Yanliang Wang, Fengyu Wang, Jiewen Zhang *These authors contributed equally to this work.
De novo Mutation Enables NOTCH3ECD Aggregation and Mitochondrial Dysfunction via Interactions with BAX and BCL-2
Abstract: Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear. Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL. Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis. Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G>A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis. Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations.

Pages 83-109
Ruth Benca, W. Joseph Herring, Rezaul Khandker, Zaina Qureshi (Handling Associate Editor: Daniela Galimberti)
Burden of Insomnia and Sleep Disturbances and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer’s Disease: A Structured Literature Review
Abstract: Background: Sleep disturbances are frequent in Alzheimer’s disease (AD). Objective: To summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies. Methods: Published studies (January 1985–March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase, and Cochrane Library and screened against inclusion criteria. Results: 58 studies assessing patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances were identified. Sleep disturbances were associated with worse cognition, functional ability, and behavioral and neuropsychological functioning. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g., cognitive status). Bright light and behavioral therapies as well as drugs showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to the effect on associated clinical burden. Conclusion: Sleep disturbances are a significant problem for AD patients and caregivers, associated with behavioral and psychological problems and cognitive decline. However, they remain poorly characterized and under-researched. As the global population is aging and AD is on the rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact insomnia treatments can have.

Pages 111-123
Zhihong Bian, Xia Liu, Tian Feng, Haibo Yu, Xiao Hu, Xinran Hu, Yuting Bian, Hongming Sun, Koh Tadokoro, Mami Takemoto, Taijun Yunoki, Yumiko Nakano, Yusuke Fukui, Ryuta Morihara, Koji Abe, Toru Yamashita
Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer’s Disease Mice
Abstract: Background: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer’s disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. Objective: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD+CAA mice model. Methods: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. Results: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD+CAA mice model compared with warfarin and no-treatment groups. Conclusion: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

Pages 125-134
Qiaoyang Zhang, Min Zhang, Yun Chen, Yin Cao*, Guanzhong Dong* *These authors contributed equally to this work.
Nonlinear Relationship of Non-High-Density Lipoprotein Cholesterol and Cognitive Function in American Elders: A Cross-Sectional NHANES Study (2011–2014)
Abstract: Background: Serum non-high-density lipoprotein-cholesterol (non-HDL-C) levels may be associated with cognitive function. Objective: The objective of this study was to evaluate the association between non-HDL-C and cognitive function among American elders. Methods: We used data from the 2011 to 2014 U.S. National Health and Nutrition Examination Survey (NHANES). A total of 3,001 participants aged over 60 years were enrolled in our analysis. The cognitive function was evaluated with the word learning subtest from the Consortium to Establish a Registry for Alzheimer's disease (CERAD W-L), the Animal Fluency Test (AFT), and the digit symbol substitution test (DSST). We also created a composite cognitive z-score to represent a global cognition. We applied multivariate linear regression analyses to estimate the associations between non-HDL-C levels and all domains of cognitive function. Further, the generalized additive model and the smooth curve were conducted to investigate the dose-response relationship between non-HDL-C and global cognition. Results: Serum non-HDL-C was positively associated with global cognition (β = 0.20, 95%CI: 0.11, 0.28), AFT score (β = 0.54, 95%CI: 0.33, 0.76), and DSST score (β = 1.13, 95%CI: 0.56, 1.69) after fully adjusted. While non-HDL-C was not related to CERAD W-L score. In addition, an inverted U-shape curve was observed in the dose-response relationship between non-HDL-C and global cognition (p for non-linearity < 0.001). Conclusion: Serum non-HDL-C is positively and nonlinearly associated with cognitive function among American older adults. Maintaining serum cholesterol levels at an appropriate range may be helpful to the cognitive health of the elderly.

Pages 135-153
Catherine Henderson, Martin Knapp, Anthony Martyr, Laura D. Gamble, Sharon M. Nelis, Catherine Quinn, Claire Pentecost, Rachel Collins, Yu-Tzu Wu, Ian R. Jones, Christina R. Victor, James A. Pickett, Roy W. Jones, Fiona E. Matthews, Robin G. Morris, Jennifer Rusted, Jeanette M. Thom, Linda Clare on behalf of the IDEAL programme team (Handling Associate Editor: Anders Wimo)
The Use and Costs of Paid and Unpaid Care for People with Dementia: Longitudinal Findings from the IDEAL Cohort
Abstract: Background: The drivers of costs of care for people with dementia are not well understood and little is known on the costs of care for those with rarer dementias. Objective: To characterize use and costs of paid and unpaid care over time in a cohort of people with dementia living in Britain. To explore the relationship between cohort members’ demographic and clinical characteristics and service costs. Methods: We calculated costs of health and social services, unpaid care, and out-of-pocket expenditure for people with mild-to-moderate dementia participating in three waves of the IDEAL cohort (2014-2018). Latent growth curve modelling investigated associations between participants’ baseline sociodemographic and diagnostic characteristics and mean weekly service costs. Results: Data were available on use of paid and unpaid care by 1,537 community-dwelling participants with dementia at Wave 1, 1,199 at Wave 2, and 910 at Wave 3. In models of paid service costs, being female was associated with lower baseline costs and living alone was associated with higher baseline costs. Dementia subtype and caregiver status were associated with variations in baseline costs and the rate of change in costs, which was additionally influenced by age. Conclusion: Lewy body and Parkinson's disease dementias were associated with higher service costs at the outset, and Lewy body and frontotemporal dementias with more steeply increasing costs overall, than Alzheimer’s disease. Planners of dementia services should consider the needs of people with these relatively rare dementia subtypes as they may require more resources than people with more prevalent subtypes.

Pages 155-171
Ondřej Lerch, Martina Laczó, Martin Vyhnálek, Zuzana Nedelská, Jakub Hort, Jan Laczó
APOE ε4 Allele Moderates the Association Between Basal Forebrain Nuclei Volumes and Allocentric Navigation in Older Adults Without Dementia
Abstract: Background: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer’s disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOE ε4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. Objective: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. Methods: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). Results: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1-2=0.039; pch4p=0.042) and PFC (pch4ai=0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p=0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p=0.035). Conclusion: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.

Pages 173-190
Jessica L. Dennison, Claude-Henry Volmar, Danbing Ke, James Wang, Emilie Gravel, Sabrina Hammond-Vignini, Zuomei Li, James A. Timmons, Ines Lohse, Marshall A. Hayward, Shaun P. Brothers, Claes Wahlestedt (Handling Associate Editor: M. Paul Murphy)
JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model
Abstract: Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROL™, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Pages 191-204
Li-Na Zhang, Meng-Jie Li, Ying-Hui Shang, Yun-Ru Liu, Han-Chang Huang, Feng-Xue Lao
Zeaxanthin Attenuates the Vicious Circle Between Endoplasmic Reticulum Stress and Tau Phosphorylation: Involvement of GSK-3β Activation
Abstract: Background: Alzheimer's disease (AD) characterized by neurofibrillary tangles caused by hyperphosphorylated tau is the most common cause of dementia. Zeaxanthin (Zea), derived from fruits and vegetables, may reduce the risk of AD. Endoplasmic reticulum stress (ERS) might cause memory impairment in AD. Objective: Here, we studied protective role of Zea on the relationship among ERS, activity of glycogen synthase kinase 3β (GSK-3β, tau phosphorylated kinase), and p-Tau (Ser 396 and Thr 231). Methods: The results were obtained in non-RA and RA group by using different treatment, such as 9-cis-retinoic acid (RA), TM (ERS inducer), Zea, 4-PBA (ERS inhibitor), and SB216763 (GSK-3β inhibitor). The methods included flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] for the detections of cell cycle and cell viability and western blot as a third measure of proteins in relation to ERS and tau phosphorylation. We have collected and analyzed all the data that suggested application of drugs for the treatment in non-RA and RA group. Results: Zea displays its protection on TM-induced cell injury, upregulation of GRP78 expression, and change of GSK-3β activity and tau phosphorylation when 4-PBA and SB216763 interfere with the process. Conclusion: These studies indicated that Zea is in vicious circle in ERS, GSK-3β, and tau phosphorylation, and further reflect its potential value in AD.

Pages 205-218
Enrico Premi, Tommaso Costa, Stefano Gazzina, Alberto Benussi, Franco Cauda, Roberto Gasparotti, Silvana Archetti, Antonella Alberici, John C. van Swieten, Raquel Sanchez-Valle, Fermin Moreno, Isabel Santana, Robert Laforce, Simon Ducharme, Caroline Graff, Daniela Galimberti, Mario Masellis, Carmela Tartaglia, James B. Rowe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Rik Vandenberghe, Alexander Gerhard, Chris R. Butler, Adrian Danek, Matthis Synofzik, Johannes Levin, Markus Otto, Roberta Ghidoni, Giovanni Frisoni, Sandro Sorbi, Georgia Peakman, Emily Todd, Martina Bocchetta, Johnathan D. Rohrer, Barbara Borroni, on behalf of the Genetic FTD Initiative (GENFI)
An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers
Abstract: Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.216.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power=0.80, alpha=0.05). Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself.

Pages 219-229
Madhumitha Manivannan, Julia Heunis, Sarah M. Hooper, Alissa Bernstein Sideman, Kristi P. Lui, Tamara L. Braley, Katherine L. Possin, Winston Chiong
Use of Telephone- and Internet-Based Support to Elicit and Address Financial Abuse and Mismanagement in Dementia: Experiences from the Care Ecosystem Study
Abstract: Background: Financial mismanagement and abuse in dementia have serious consequences for patients and their families. Vulnerability to these outcomes reflects both patient and contextual factors. Objective: Our study aimed to assess how multidisciplinary care coordination programs assist families in addressing psychosocial vulnerabilities and accessing needed resources. Methods: Our study was embedded in a clinical trial of the Care Ecosystem, a telephone- and internet-based supportive care intervention for patients with dementia and caregivers. This program is built around the role of the Care Team Navigator (CTN), an unlicensed dementia care guide who serves as the patient and caregiver's primary point of contact, screening for common problems and providing support. We conducted a qualitative analysis of case summaries from a subset of 19 patient/caregiver dyads identified as having increased risk for financial mismanagement and abuse, to examine how Care Ecosystem staff identified vulnerabilities and provided support to patients and families. Results: CTNs elicited patient and caregiver needs using templated conversations to address common financial and legal planning issues in dementia. Sources of financial vulnerability included changes in patients' behavior, caregiver burden, intrafamily tension, and confusion about resources to facilitate end-of-life planning. The Care Ecosystem staff’s rapport with their dyads helped them address these issues by providing emotional support, information on how to access financial, medical, and legal resources, and improving intra-familial communication. Conclusion: The Care Ecosystem offers a scalable way to address vulnerabilities to financial mismanagement and abuse in patients and caregivers through coordinated care by unlicensed care guides supported by a multidisciplinary team.

Pages 231-244
Fatima Siddiqui*, Kameswara Rishi Yeshayahu Nistala*, Chrystie Wan Ning Quek, Victoria Shi Ying Leong, Amarinda Ying Shan Tan, Christopher Yu En Tan, Saima Hilal (Handling Associate Editor: Gabrielle Britton) *These authors contributed equally to this work.
Knowledge, Attitudes, and Perceptions Toward Dementia Among Middle-Aged Singapore Residents
Abstract: Background: Dementia is the decline in cognitive function sufficient to impair one’s accustomed functioning. Countries with aging populations, such as Singapore, face rising rates of dementia. Dementia patients and their caregivers endure great financial and emotional stress. With the broad aim of minimizing these stresses, this study provides a cross-sectional view of the knowledge, attitudes, and perceptions (KAP) towards dementia in middle-aged Singaporean residents. Objective: We aim to examine 1) the associations between demographic correlates and KAP; and 2) the effect of dementia knowledge on attitudes and perceptions towards dementia. Methods: An online anonymous cross-sectional questionnaire was administered to Singaporeans and Permanent Residents aged 45 to 65 years old in English, Mandarin, and Malay. Knowledge was evaluated across three domains: symptoms, risk factors, and management. Total and domain scores were dichotomized as good or poor knowledge using median cut-offs. Attitudes/perceptions across six domains were evaluated on Likert scales, and responses to each question were dichotomized into positive or negative attitudes/perceptions. Results: From 1,733 responses, 1,209 valid complete responses were accepted (mean age±SD 54.8±5.12 years old, females=69.6%). Lower socioeconomic status was associated with poorer knowledge and greater barriers to risk-mitigating lifestyle modifications. Lack of personal experience with dementia and poor knowledge were also associated with erroneous attitudes/perceptions. Conclusion: Socioeconomic status and personal experience affect KAP towards dementia. Policy and education campaigns to address KAP towards dementia should account for baseline differences across demographics, for greater improvements in dementia incidence and support.

Pages 245-257
Juraj Secnik, Hong Xu, Emilia Schwertner, Niklas Hammar, Michael Alvarsson, Bengt Winblad, Maria Eriksdotter, Sara Garcia-Ptacek, Dorota Religa
Glucose-Lowering Medications and Post-Dementia Survival in Patients with Diabetes and Dementia
Abstract: Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95% CI 1.24-1.45]) as well as in dementia-free subjects (1.54 [1.10-1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01-1.42]). GLP-1a (0.44 [0.25-0.78]) and SGLT-2i users with dementia (0.43 [0.23-0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients.

Pages 259-270
Bizhong Che*, Haichang Chen*, Aili Wang, Hao Peng, Xiaoqing Bu, Jintao Zhang, Zhong Ju, Tan Xu, Jiang He, Chongke Zhong, Yonghong Zhang *These authors contributed equally to this work.
Association Between Plasma L-Carnitine and Cognitive Impairment in Patients with Acute Ischemic Stroke
Abstract: Background: L-carnitine has been shown to exert neuroprotective effects on cerebral ischemia, mainly by improving mitochondrial function and reducing inflammation. L-carnitine supplementation has also been promoted to enhance cognitive function. However, the relationship between L-carnitine and cognitive impairment after ischemic stroke has seldom been studied. Objective: We aimed to evaluate the association between plasma L-carnitine and poststroke cognitive impairment. Methods: The study sample population was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke. Plasma L-carnitine were measured at baseline in 617 patients with ischemic stroke using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Cognitive function was evaluated using the Montreal Cognitive Assessment at 3-month follow-up after ischemic stroke. Results: Plasma L-carnitine were inversely associated with cognitive impairment at 3 months after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartiles of L-carnitine was 0.60 (0.37, 0.98; p for trend=0.04). Each 1-SD increase in log-transformed L-carnitine concentration was significantly associated with a 15% (95% CI: 1%, 29%) reduction in the risk of cognitive impairment after stroke. The addition of L-carnitine to the model including conventional risk factors significantly improved the risk reclassification for cognitive impairment (net reclassification improvement: 17.9%, integrated discrimination improvement: 0.8%; both p<0.05). Furthermore, joint effects of L-carnitine and inflammation markers were observed, and patients with higher L-carnitine and a lower inflammatory status simultaneously had the lowest risk of poststroke cognitive impairment. Conclusion: The present study provided prospective evidence on the inverse association between plasma L-carnitine and cognitive impairment after ischemic stroke.

Pages 271-281
Jeff Schaffert, Christian LoBue, Linda S. Hynan, John Hart, Jr., Heidi Rossetti, Anne R. Carlew, Laura Lacritz, Charles L. White, III, C. Munro Cullum (Handling Associate Editor: Melissa Lamar)
Predictors of Life Expectancy in Autopsy-Confirmed Alzheimer’s Disease
Abstract: Background: Life expectancy (LE) following Alzheimer’s disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses. Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study. Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer’s Coordinating Center (N=1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death. Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12. Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD.

Pages 283-296
Justin Miron, Cynthia Picard, Anne Labonté, Daniel Auld, Judes Poirier for the PREVENT-AD research group
MSR1 and NEP Are Correlated with Alzheimer’s Disease Amyloid Pathology and Apolipoprotein Alterations
Abstract: Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ1-42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1, APOE, and CLU (APOJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ1-42, ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ1-42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages.

Pages 297-313
Wei Zhang, Minghui Zhang, Qin Wu, Jingshan Shi
Dendrobium nobile Lindl. Alkaloids Ameliorate Aβ25-35-Induced Synaptic Deficits by Targeting Wnt/β-Catenin Pathway in Alzheimer’s Disease Models
Abstract: Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway. Methods: Sprague-Dawley rats received a single Aβ25-35 injection (10 µg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95. Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity.

Pages 315-331
Mingjing Liu, Shipeng Guo, Daochao Huang, Dongjie Hu, Yili Wu, Weihui Zhou, Weihong Song (Handling Associate editor: Ling-Qiang Zhu)
Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice
Abstract: Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

Pages 333-341
Elizabeta B. Mukaetova-Ladinska, Shahbaz Abdullah, Mathew Critchfield, John Maltby
Suspected Dementia in Young Adults: Cognitive Screening Tools for Use in Primary Care
Abstract: Background: Memory complaints are frequent among young adults presenting in general practice. Many of them will have reversable, functional cognitive impairment that can easily be mistaken for dementia. Its accurate and timely identification is warranted to prevent further escalation to overt dementia syndrome. Objective: To evaluate the recommended primary care screening cognitive tools for dementia for use in younger people. Methods: 2.5 years clinical data were collected during the course of ongoing patient care for all assessed face-to-face patients in a secondary care memory service for younger adults. Cognitive screening and assessment tests used in primary [General Practice Assessment of Cognition (GPCOG)] and secondary [Addenbrooke’s Cognitive Examination-III (ACE-III), Rowland Universal Dementia Assessment Scale (RUDAS), Salzburg Dementia Test Prediction (SDTP)] care were analyzed for their accuracy to identify dementia and memory complaints. Area under the curve in receiver operating characteristic curves was used to measure predictive value of tests for a clinical diagnosis of dementia. Results: 348 young adults were assessed for cognitive impairment. Following comprehensive Memory Clinic assessments, 241 (69.25%) were diagnosed with memory complaints in the absence of relevant neuropathology and 107 with dementia. GPCOG, especially the informant part, and RUDAS had low accuracy to identify dementia (AUC=0.465 and AUC=0.698, respectively). In contrast, ACE-III and SDTP demonstrated the highest accuracy (AUC=0.799 and AUC=0.809/0.817, respectively). Conclusion: Dementia screening in younger people will benefit from SDTP incorporated as part of the screening cognitive toolset. The national guidance on dementia screening tools, diagnostic pathways, and management should also refer to younger adults.

Pages 343-364
Anna Barlach Pritchard, Zsolt Fabian, Clare L. Lawrence, Glyn Morton, StJohn Crean, Jane E. Alder
An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model
Abstract: Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).

Pages 365-386
Guillermo Eastman, Elizabeth R. Sharlow, John S. Lazo, George S. Bloom, José R. Sotelo-Silveira
Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice
Abstract: Background: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2-/-) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

Pages 387-402
Fátima Mesa-Herrera, Raquel Marín, Eduardo Torrealba, Mario Díaz
Multivariate Assessment of Lipoxidative Metabolites, Trace Biometals, and Antioxidant and Detoxifying Activities in the Cerebrospinal Fluid Define a Fingerprint of Preclinical Stages of Alzheimer’s Disease
Abstract: Background: There exists considerable interest in the identification of molecular traits during early stages of Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is considered the closest prodromal stage of AD, and to develop gradually from earlier stages although not always progresses to AD. Classical cerebrospinal fluid (CSF) AD biomarkers, amyloid-β peptides and tau/p-tau proteins, have been measured in prodromal stages yet results are heterogeneous and far from conclusive. Therefore, there exists a pressing need to identify a neurochemical signature for prodromal stages and to predict which cases might progress to AD. Objective: Exploring potential CSF biomarkers related to brain oxidative and inorganic biochemistry during prodromal stages of the disease. Methods: We have analyzed CSF levels of lipoxidative markers (MDA and 8-isoF2α), biometals (Cu, Zn, Se, Mn, and Fe), iron-transport protein transferrin (TFER), antioxidant enzymes (SOD and GPx4), detoxifying enzymes (GST and BuChE), as well as classical amyloid-β and total and phosphorylated tau, in cognitively healthy controls, patients with MCI, and subjects exhibiting subjective memory complaints (SMC). Results: Inter-group differences for several variables exhibit differentiable trends along the HC→SMC→MCI sequence. More interestingly, the combination of Se, Cu, Zn, SOD, TFER, and GST variables allow differentiable fingerprints for control subjects and each prodromal stage. Further, multivariate scores correlate positively with neurocognitive In-Out test, hence with both episodic memory decline and prediction to dementia. Conclusion: We conclude that changes in the CSF biochemistry related to brain oxidative defense and neurometallomics might provide more powerful and accurate diagnostic tools in preclinical stages of AD.

Pages 403-411
Antonio L. Teixeira, Haitham Salem, Lais B. Martins, Mitzi M. Gonzales, Sudha Seshadri, Robert Suchting
Factors Associated with Apathy in Alzheimer’s Disease: A Cross-Sectional Analysis of the Texas Alzheimer’s Research and Care Consortium (TARCC) Study
Abstract: Background: Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer’s disease (AD). Objective: To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Methods: This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory–Questionnaire applied to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. Results: From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Conclusion: Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation.

Pages 413-424
Marilyn Reed, Morris Freedman, Amy E. Mark Fraser, Matthew Bromwich, Anna Theresa Santiago, Christina Elizabeth Gallucci, Andrew Frank
Enhancing Clinical Visibility of Hearing Loss in Cognitive Decline
Abstract: Background: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults. Objective: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians’ awareness of hearing loss and improve access to timely hearing care. Methods: Patients referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology. Results: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology. Conclusion: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia.

Pages 425-440
Nils Richter, Lara-Sophia David, Michel J. Grothe, Stefan Teipel, Markus Dietlein, Marc Tittgemeyer, Bernd Neumaier, Gereon R. Fink, Oezguer A. Onur*, Juraj Kukolja* *These authors contributed equally to this work.
Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer’s disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. Objective: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. Methods: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Results: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman’s rho(17) = -0.596, 95%-CI [-0.905, -0.119] and 0.593, 95%-CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Conclusion: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Pages 441-450
Bo Kyung Sohn, Min Soo Byun, Dahyun Yi, So Yeon Jeon, Jun Ho Lee, Young Min Choe, Dong Woo Lee, Jun-Young Lee, Yu Kyeong Kim, Chul-Ho Sohn, Dong Young Lee, for the KBASE Research Group
Late-Life Physical Activities Moderate the Relationship of Amyloid-β Pathology with Neurodegeneration in Individuals Without Dementia
Abstract: Background: Physical activities (PA) have been suggested to reduce the risk of Alzheimer's disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. Objective: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. Methods: This study included participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer’s disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. Results: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. Conclusion: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults.

Pages 451-460
Frederik Nørregaard Pedersen, Lonny Stokholm, Frans Pouwer, Katrine Hass Rubin, Tunde Peto, Ulrik Frydkjær-Olsen, Anne Suhr Thykjær, Nis Andersen, Jens Andresen, Toke Bek, Morten la Cour, Steffen Heegaard, Kurt Højlund, Ryo Kawasaki, Javad Nouri Hajari, Kirsten Ohm Kyvik, Caroline Schmidt Laugesen, Katja Christina Schielke, Rafael Simó, Jakob Grauslund
Diabetic Retinopathy Predicts Risk of Alzheimer’s Disease: A Danish Registry-Based Nationwide Cohort Study
Abstract: Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer’s disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.

Pages 461-477
Pavel P. Kuksa*, Chia-Lun Liu*, Wei Fu, PhD*, Liming Qu, Yi Zhao, Zivadin Katanic, Kaylyn Clark, Amanda B. Kuzma, Pei-Chuan Ho, Kai-Teh Tzeng, Otto Valladares, Shin-Yi Chou, Adam C. Naj, Gerard D. Schellenberg, Li-San Wang**, Yuk Yee Leung** (Handling Associate Editor: Anthony Griswold) *,**These authors contributed equally to this work.
Alzheimer’s Disease Variant Portal: A Catalog of Genetic Findings for Alzheimer’s Disease
Abstract: Background: Recent Alzheimer’s disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations. Objective: Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations. Methods: We developed the Alzheimer’s Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer’s Disease Genetics Consortium and other consortia. Genetic associations were systematically extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories. Results: ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings. Conclusion: ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org.

Pages 479-490
Boaz Levy, Amanda Priest, Tyler Delaney, Jacqueline Hogan, Farahdeba Herrawi
Toward Pre-Diagnostic Detection of Dementia in Primary Care
Abstract: Background: Preventing dementia warrants the pragmatic engagement of primary care. Objective: This study predicted conversion to dementia 12 months before diagnosis with indicators that primary care can utilize within the practical constraints of routine practice. Methods: The study analyzed data from the Alzheimer’s Disease Neuroimaging Initiative (Total sample=645, converting participants=54). It predicted the conversion from biological (plasma neurofilament light chain), cognitive (Trails Making Test–B), and functional (Functional Activities Questionnaire) measures, in addition to demographic variables (age and education). Results: A Gradient Booster Trees classifier effectively predicted the conversion, based on a Synthetic Minority Oversampling Technique (n=1,290, F1 Score=92, AUC=94, Recall=87, Precision=97, Accuracy= 92). Subsequent analysis indicated that the MCI False Positive group (i.e., non-converting participants with cognitive impairment flagged by the model for prospective conversion) scored significantly lower on multiple cognitive tests (Montreal Cognitive Assessment, p<0.002; ADAS-13, p<0.0004; Rey Auditory Verbal Learning Test, p<0.002/0.003) than the MCI True Negative group (i.e., correctly classified non-converting participants with cognitive impairment). These groups also differed in CSF tau levels (p<0.04), while consistent effect size differences emerged in the all-pairwise comparisons of hippocampal volume and CSF Aβ1-42. Conclusion: The model effectively predicted 12-month conversion to dementia and further identified non-converting participants with MCI, in the False Positive group, at relatively higher neurocognitive risk. Future studies may seek to extend these results to earlier prodromal phases. Detection of dementia before diagnosis may be feasible and practical in primary care settings, pending replication of these findings in diverse clinical samples.

Pages 491-498
Kennedy A. Josephs, Nha Trang Thu Pham, Jonathan Graff-Radford, Mary M. Machulda, Val J. Lowe, Jennifer L. Whitwell
Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign
Abstract: Background: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). Objective: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. Methods: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Results: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. Conclusion: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

Pages 499-507
M. Windy McNerney, Alesha Heath, Sindhu Narayanan, Jerome Yesavage
Repetitive Transcranial Magnetic Stimulation Improves Brain-Derived Neurotrophic Factor and Cholinergic Signaling in the 3xTgAD Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a debilitating disorder involving the loss of plasticity and cholinergic neurons in the cortex. Pharmaceutical treatments are limited in their efficacy, but brain stimulation is emerging as a treatment for diseases of cognition. More research is needed to determine the biochemical mechanisms and treatment efficacy of this technique. Objective: We aimed to determine if forebrain repetitive transcranial magnetic stimulation can improve cortical BDNF gene expression and cholinergic signaling in the 3xTgAD mouse model of AD. Methods: Both B6 wild type mice and 3xTgAD mice aged 12 months were given daily treatment sessions for 14 days or twice weekly for 6 weeks. Following treatment, brain tissue was extracted for immunological stains for plaque load, as well as biochemical analysis for BDNF gene expression and cholinergic signaling via acetylcholinesterase and choline acetyltransferase ELISA assays. Results: For the 3xTgAD mice, both 14 days and 6 weeks treatment regimens resulted in an increase in BDNF gene expression relative to sham treatment, with a larger increase in the 6-week group. Acetylcholinesterase activity also increased for both treatments in 3xTgAD mice. The B6 mice only had an increase in BDNF gene expression for the 6-week group. Conclusion: Brain stimulation is a possible non-invasive and nonpharmaceutical treatment option for AD as it improves both plasticity markers and cholinergic signaling in an AD mouse model.

Pages 509-510
Book Review

How Not to Study a Disease: The Story of Alzheimer’s by Karl Herrup, The MIT Press, 2021, 245 pp. Reviewed by Daniel R. George and Peter J. Whitehouse