Volume 93, Number 3, IN PRESS

Wesley Wei-Wen Hsiao#, Stefanny Angela#, Trong-Nghia Le, Chia-Chi Ku, Po-Sheng Hu, Wei-Hung Chiang #These authors contributed equally to this work.
Evolution of Detecting Early Onset of Alzheimer’s Disease: From Neuroimaging to Optical Immunoassays
Abstract: Alzheimer's disease (AD) is a pathological disorder defined by the symptoms of memory loss and deterioration of cognitive abilities over time. Although the etiology is complex, it is mainly associated with the accumulation of toxic amyloid-β peptide (Aβ) aggregates and tau protein-induced neurofibrillary tangles (NFTs). Even now, creating non-invasive, sensitive, specific, and cost-effective diagnostic methods for AD remains challenging. Over the past few decades, polymers, and nanomaterials (e.g., nanodiamonds, nanogold, quantum dots) have become attractive and practical tools in nanomedicine for diagnosis and treatment. This review focuses on current developments in sensing methods such as enzyme-linked immunosorbent assay (ELISA) and surface-enhanced Raman scattering (SERS) to boost the sensitivity in detecting related biomarkers for AD. In addition, optical analysis platforms such as ELISA and SERS have found increasing popularity among researchers due to their excellent sensitivity and specificity, which may go as low as the femtomolar range. While ELISA offers easy technological usage and high throughput, SERS has the advantages of improved mobility, simple electrical equipment integration, and lower cost. Both portable optical sensing techniques are highly superior in terms of sensitivity, specificity, human application, and practicality, enabling the early identification of AD biomarkers.

Rui Liu, Lei Zhang, Hao You
Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer’s Disease
Abstract: The pathogenesis of Alzheimer’s disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington’s disease, Parkinson’s disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD.

Kexin Zhang, Xinzhe Du, Yao Gao, Sha Liu, Yong Xu
Mesenchymal Stem Cells for Treating Alzheimer’s Disease: Cell Therapy and Chemical Reagent Pretreatment
Abstract: As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer’s disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients’ life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs.

Charlotte Nijskens, Marieke Henstra, Hanneke Rhodius-Meester, Sevil Yasar, Eveline van Poelgeest, Mike Peters, Majon Muller
Cardiovascular Risk Management in Persons with Dementia
Abstract: The number of people living with dementia, such as Alzheimer’s disease, is increasing worldwide. Persons with dementia often have a high risk of atherosclerotic cardiovascular disease and they are therefore theoretically eligible for treatment of hypertension and hyperlipidemia. However, in this population, beneficial and harmful effects of cardiovascular risk management (CVRM) may be different compared to older persons without cognitive impairment. Current CVRM guidelines are based on trials from which persons with dementia were excluded. In this narrative review, we will discuss how current guidelines can be translated to persons with dementia and which aspects should be taken into account when treating hypertension and hyperlipidemia to prevent major adverse cardiovascular events (MACE). Survival time is significantly shorter in persons with dementia. We therefore suggest that since the main goal of CVRM is prevention of MACE, first of all, the patient’s life expectancy and treatment wishes should be evaluated. Risk assessment tools are to be used with care, as they tend to overestimate the 5- and 10-year risk of MACE and benefit from CVRM in the prevention of MACE in persons with dementia. When the clinician and patient have decided that treatment is initiated or intensified, patients should be closely monitored since they are at high risk for adverse drugs events and overtreatment due to the natural course of blood pressure in persons with dementia. In the event of intolerance or side effects, medication should be switched or withdrawn. For persons with dementia and limited life expectancy, deprescribing should be part of usual care.

Systematic Review
Dorothee Bauernschmidt, Julian Hirt, Gero Langer, Gabriele Meyer, Susanne Unverzagt, Fabian Wilde, Janina Wittmann, Anja Bieber
Technology-Based Counselling for People with Dementia and Their Informal Carers: A Systematic Review and Meta-Analysis
Abstract: Background: Information technology can enhance timely and individual support for people with Alzheimer's disease and other dementias and their informal carers. Objective: To review the effectiveness of technology-based counselling interventions for people with dementia and informal carers. Methods: Randomized controlled trials of remote dementia counselling interventions were included. We searched CINAHL, Cochrane Library, MEDLINE, PsycINFO, and the Web of Science Core Collection (April 2021) in combination with citation tracking and free web searching (October to November 2021). We provide meta-analyses for caregiver depression, burden, and self-efficacy/mastery and structured reporting for other outcomes. The Grading of Recommendations Assessment, Development and Evaluation approach and the Risk of Bias 2 tool were applied. Results: We included five randomized controlled trials involving 880 participants. Interventions were provided for carers (four studies) or dyads (one study). Carers were predominantly women and were the spouses or children of people with dementia. Counselling was delivered via telephone or videoconference with two to 23 sessions over 1 to 12 months. Control groups received educational and resource materials only, standard (helpline) services, non-directive support, or home visits. Meta-analysis for our primary outcome, depressive symptoms in carers, revealed no statistically significant effect (SMD -0.15; 95% CI -0.40 to 0.10). There were also no significant effects on burden and self-efficacy/mastery. We rated the certainty of evidence as low to very low and all outcomes at an overall high risk of bias. Conclusion: The effectiveness of technology-based counselling interventions for people with dementia and informal carers remains uncertain. Theory-based approaches are needed for the development and evaluation of these interventions.

Carr J. Smith, J. Wesson Ashford
Apolipoprotein ε4-Associated Protection Against Pediatric Enteric Infections is a Survival Advantage in Pre-Industrial Populations
Abstract: Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ε4/ε4 genotype, when the ε3 allele mutated from the ancestral ε4, which elevates the risk of Alzheimer’s disease. Modern humans living today predominantly carry the ε3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ε4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host’s defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ε4 carriers, yet ε4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ε3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer’s disease.

Christopher J. Wheeler
Evolutionary Selection of APOE ε4 Encourages Increased Focus on Immunity in Alzheimer’s Disease
Abstract: Smith and Ashford present a compelling hypothesis on evolution of APOE alleles, namely that ε4 prevalence is mediated by immune selection pressure against enteric pathogens. While the ε3 allele is more prevalent today, it outcompeted ε4 only relatively recently, as immune selection pressure for more effective immune responses to such pathogens was alleviated with transition to agrarian from hunter-gatherer lifestyles. Smith and Ashford’s hypothesis is intriguing in itself, but the implications for APOE ε4 function in Alzheimer’s disease are even more so and encourage greater focus on specific aspects of immunity in accounting for both ε4-mediated and general Alzheimer’s disease risk.

Mathieu Maltais
Exercise for Preventing Falls in People with Dementia: Time to Work Together
Abstract: Since the last two decades, many systematic reviews and meta-analyses found contradicting results on the effect of exercise in reducing falls in people with dementia. The recently published systematic review in the Journal of Alzheimer’s Disease found positive results in reducing falls in only two studies. The authors conclude that insufficient data remains in reducing the number of falls by exercise interventions. This commentary focuses on interdisciplinary approaches that could reduce the number of falls in this vulnerable population.

Eric Dinnersetin
The Time for Combination Therapy Research in Alzheimer’s Disease is Now

Giovanna Pilonieta, Maria Pisu, Roy C. Martin, Liang Shan, Richard E. Kennedy, Gabriela Oates, Young-Il Kim, David S. Geldmacher
Specialist Availability and Drug Adherence in Older Adults with Dementia Across Regions of the United States
Abstract: Background: Access to specialists facilitates appropriate Alzheimer’s disease and related dementia (ADRD) medication use and adherence. However, there is little information on the impact of specialists’ availability on ADRD medication adherence, especially in regions of the United States (US) where specialists are scarce, e.g., the Deep South (DS). Objective: To ascertain whether the availability of specialty physicians in the DS and other US regions predicts ADRD medication adherence among community-dwelling older adults Methods: We conducted secondary analyses of claims data for 54,194 Medicare beneficiaries with ADRD in 2013-2015. Medication adherence was measured using the proportion of days covered (PDC). Multivariable-adjusted Modified Poisson regression was used to examine associations of adherence with physicians' availability by region. Results: The race/ethnicity distribution was 81.44% white, 9.17% black, 6.24% Hispanic, 2.25% Asian, and 1% other; 71.81% were female, and 42.36% were older than 85 years. Beneficiaries across regions differed in all individual and contextual characteristics except sex and comorbidities. Neurologists and psychiatrists’ availability was not significantly associated with adherence (DS=1.00, 0.97-1.03 & non-DS=1.01, 1.00-1.01). Race and having ≥1 specialist visits were associated with a lower risk of adherence in both regions (p<0.0001). Advanced age, dual Medicare/Medicaid eligibility, and living in non-large metropolitan areas, were associated with adherence in the non-DS region. Conclusion: Among older Americans with ADRD, a context defined by specialist availability does not affect adherence, but other context characteristics related to socioeconomic status may. Research should further examine the influence of individual and contextual factors on ADRD treatment among older adults.

Daniel Zvi Press*, Christian Sandøe Musaeus*, Li Zhao, Jocelyn Breton, Mouhsin M. Shafi, Weiying Dai, David C. Alsop *These authors contributed equally to this work.
Levetiracetam Increases Hippocampal Blood Flow in Alzheimer’s Disease as Measured by Arterial Spin Labelling MRI
Abstract: Background: Patients with Alzheimer’s disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. Objective: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. Methods: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n=9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI. Results: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. Conclusion: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.

Laura E. Gibbons, Melinda C. Power, Rod L. Walker, Raj G. Kumar, Alia Murphy, Caitlin S. Latimer, Amber L. Nolan, Erica J. Melief, Allison Beller, Marika Bogdani, C. Dirk Keene, Eric B. Larson, Paul K. Crane, Kristen Dams-O’Connor
Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort
Abstract: Background: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. Objective: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Methods: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ε4 genotype were weighted back to the full cohort of 5,546 participants. Results: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. Conclusion: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer’s disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer’s disease.

Lon R. White
If Midlife Brain Injury Is a Risk Factor for Alzheimer's Disease and Related Dementias, What Is the Neuropathologic Mechanism?
Abstract: While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer's Disease and Related Dementias (ADRD). Published analytic conclusions have been mixed. Two reports in the Journal of Alzheimer’s Disease reach the same answer: a history of brain injury appears to be a risk factor for generalized brain atrophy, which would likely increase vulnerability to the subsequent development of any variety of ADRD, or to dementia directly attributable to reduced brain mass.

Chetna Malhotra, Ishwarya Balasubramanian on behalf of the PISCES study group
Caregivers’ End-of-Life Care Goals for Persons with Severe Dementia Change Over Time
Abstract: Background: Family caregivers make end-of-life (EOL) decisions for persons with severe dementia (PWSDs). It is not known whether the family caregivers’ goals change over time. Objective: Assess caregivers’ EOL care goal for PWSDs and change in these goals over time. Methods: Using a prospective cohort of 215 caregivers of PWSDs, we assessed the proportion of caregivers whose EOL care goal for PWSDs changed between two consecutive time points. Mixed effects multinomial regression models assessed factors associated with caregivers’ EOL care goals for PWSD (maximal, moderate, minimal life extension); and change in EOL care goal from previous time point. Results: At baseline, 20% of the caregivers had a goal of maximal life extension for their PWSD, and 59% changed their EOL care goal at least once over a period of 16 months. Caregivers of PWSDs with lower quality of life (RR: 1.15, CI: 1.06, 1.24), who expected shorter life expectancy for PWSDs (RR: 10.34, CI: 2.14, 49.99) and who had an advance care planning discussion (RR: 3.52, CI: 1.11, 11.18) were more likely to have a goal of minimal life extension for PWSD. Caregivers with higher anticipatory grief (RR: 0.96, CI: 0.93,1) were more likely to have a goal of maximal life extension. Change in PWSDs’ quality of life and change in caregivers’ anticipatory grief were associated with change in caregivers’ EOL care goals. Conclusion: Caregivers’ EOL care goals for PWSDs change over time with change in PWSD and caregiver related factors. Findings have implications regarding how health care providers can engage with caregivers.

Rui-Qi Zhang, Ya-Nan Ou, Shu-Yi Huang, Yu-Zhu Li, Yu-Yuan Huang, Ya-Ru Zhang, Shi-Dong Chen, Qiang Dong, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu
Poor Oral Health and Risk of Incident Dementia: A Prospective Cohort Study of 425183 Participants
Abstract: Background: The association between poor oral health and the risk of incident dementia remains unclear. Objective: To investigate the associations of poor oral health with incident dementia, cognitive decline, and brain structure in a large population-based cohort study. Methods: A total of 425,183 participants free of dementia at baseline were included from the UK Biobank study. The associations between oral health problems (mouth ulcers, painful gums, bleeding gums, loose teeth, toothaches, and dentures) and incident dementia were examined using Cox proportional hazards models. Mixed linear models were used to investigate whether oral health problems were associated with prospective cognitive decline. We examined the associations between oral health problems and regional cortical surface area using linear regression models. We further explored the potential mediating effects underlying the relationships between oral health problems and dementia. Results: Painful gums (HR=1.47, 95%CI [1.317-1.647], p<0.001), toothaches (HR=1.38, 95%CI [1.244-1.538], p<0.001), and dentures (HR=1.28, 95%CI [1.223-1.349], p<0.001) were associated with increased risk of incident dementia. Dentures were associated with a faster decline in cognitive functions, including longer reaction time, worse numeric memory, and worse prospective memory. Participants with dentures had smaller surface areas of the inferior temporal cortex, inferior parietal cortex, and middle temporal cortex. Brain structural changes, smoking, alcohol drinking, and diabetes may mediate the associations between oral health problems and incident dementia. Conclusion: Poor oral health is associated with a higher risk of incident dementia. Dentures may predict accelerated cognitive decline and are associated with regional cortical surface area changes. Improvement of oral health care could be beneficial for the prevention of dementia.

James M. Noble, Panos N. Papapanou
With Teeth, Broken, or Fixed: The Challenges of Linking Periodontitis, Neuroepidemiology, and Biomarkers of Disease
Periodontitis is a chronic inflammatory, bacterially-driven disease of the tooth-supporting tissues that shares several risk factors and elements of host response with Alzheimer’s disease and related dementias (ADRD). Epidemiological studies have identified relatively consistent associations between adverse oral health conditions and ADRD. In this issue of the journal, a large study from the UK Biobank further explores these relationships along with MRI cognitive biomarkers. Despite its strength due to the large sample size, challenges in the study of periodontitis and neuroepidemiology markers include potential sampling bias, appropriate assessment of exposures, and the possibility of reverse causality.

Patrick J. Smith, Andrew Sherwood, Forgive Avorgbedor, Krista Ingle, William Kraus, Alan Hinderliter, James A. Blumenthal
Sleep Quality, Metabolic Function, Physical Activity, and Neurocognition Among Individuals with Resistant Hypertension
Abstract: Background: Resistant hypertension (RH) is a major risk factor for stroke, cognitive decline, and dementia. Sleep quality is increasingly suggested to play an important role linking RH to cognitive outcomes, although the mechanisms linking sleep quality to poor cognitive function have yet to be fully delineated. Objective: To delineate biobehavioral mechanisms linking sleep quality, metabolic function, and cognitive function among 140 overweight/obese adults with RH in the TRIUMPH clinical trial. Methods: Sleep quality was indexed using actigraphy measures of sleep quality and sleep fragmentation, as well as self-reported sleep quality from the Pittsburgh Sleep Quality Index (PSQI). Cognitive function was assessed using a 45-minute battery assessing executive function, processing speed, and memory. Participants were randomized to a cardiac rehabilitation-based lifestyle program (C-LIFE) or a standardized education and physician advice condition (SEPA) for 4 months. Results: Better sleep quality at baseline was associated with better executive function (B = 0.18 p = 0.027), as well as greater fitness (B = 0.27, p = 0.007) and lower HBA1c (B = -0.25, p = 0.010). Cross-sectional analyses revealed that the sleep quality executive function association was mediated by HBA1c (B = 0.71 [0.05, 2.05]). C-LIFE improved sleep quality (-1.1 [-1.5, -0.6] versus + -0.1 [-0.8, 0.7]) and actigraphy steps (+922 [529, 1316] versus +56 [-548, 661]), with actigraphy mediating improvements in executive function (B = 0.40 [0.02, 1.07]). Conclusion: Better metabolic function and improved physical activity patterns levels play important roles linking sleep quality and executive function in RH.

Michael Topping, Jinho Kim, Jason Fletcher
Area-Level Infant Mortality Exposure in Early Life and Alzheimer’s Disease Mortality: Examining Variation Based on Age, Sex, and Place of Birth
Abstract: Background: Growing evidence suggests that critical periods in early life may contribute to one’s risk of Alzheimer’s disease and related dementias (ADRD) in later life. In this paper we explore the role that exposure to infant mortality plays in later life ADRD. Objective: To determine if exposure to early life infant mortality is associated with later mortality from ADRD. Also, we explore how these associations differ by sex and age group, along with the role of state of birth and competing risks of death. Methods: We use a sample of over 400,000 individuals aged 50 and above with the NIH-AARP Diet and Health Study with mortality follow-up, allowing us to examine how early life infant mortality rates along with other risk factors play in one’s individual mortality risk. Results: We show that infant mortality rates are associated with death from ADRD among those under 65 years of age, but not those over 65 at baseline interview. Moreover, when factoring in competing risks of death, the associations are relatively unchanged. Conclusion: These results suggest that those exposed to worse adverse conditions during critical periods increase their likelihood of death from ADRD earlier than average, due to that exposure increasing their susceptibility to develop illness later on in life.

Michaela Defrancesco, Eberhard A. Deisenhammer, Timo A. Schurr, Markus Ortner (Handling Associate Editor: Jessica Peter)
Consequences and Perception of the COVID-19 Pandemic on Patients and Caregivers in an Austrian Memory Clinic Population One Year After Pandemic Onset
Abstract: Background: The COVID-19 pandemic was associated with high mortality and negative consequences for patients with Alzheimer's disease or dementia and their caregivers. Memory clinics play an important role in enabling early dementia diagnosis and providing support for patients and their caregivers. Objective: This study investigates the impact of the COVID-19 pandemic and its restrictions on patients of a memory clinic and their caregivers between March 2020 and March 2021. Methods: We conducted a prospective, single-center, questionnaire-based, observational study to assess consequences and perception of the COVID-19 pandemic on emotion, cognitive function, social living, areas of care, and information retrieval. Results: Results of 255 participants' (mean age 76.78, SD 8.9; 12% cognitively intact, 33% mild cognitive impairment, 55% dementia) and 203 caregivers' COVID-19 questionnaires (valid response rate 71%) could be included in the study. Participants reported a prevalence of psychological symptoms associated with the pandemic between 3-20%. Caregivers living outside compared to those living with the participant reported higher rates of new onset or worsening of neuropsychiatric symptoms in participants since pandemic onset. Patients with dementia showed the lowest use of digital communication before (15.7%) and after (17.1%) pandemic onset in the diagnostic groups. Conclusion: The COVID-19 pandemic frequently led to social isolation and reduced cognitive stimulation due to restrictions in elderly persons with cognitive deficits resulting in negative effects on emotional and social levels. We hypothesize that the implementation and sensitization with digital communication in clinical routine could provide a useful tool to counteract these negative effects.

Celina Gollop*, Rebecca Zingel*, Louis Jacob, Lee Smith, Ai Koyanagi, Karel Kostev *These authors contributed equally to this work.
Incidence of Newly-Diagnosed Dementia After COVID-19 Infection versus Acute Upper Respiratory Infection: A Retrospective Cohort Study
Abstract: Background: There is emerging evidence that coronavirus disease 2019 (COVID-19) is giving rise to seemingly unrelated clinical conditions long after the infection has resolved. Objective: The aim of this study is to examine whether COVID-19 is associated with an increased risk of dementia including Alzheimer’s disease. Methods: This retrospective cohort study is based on longitudinal data from the IQVIATM Disease Analyzer database and included patients aged ≥65 with an initial diagnosis of COVID-19 or acute upper respiratory infection (AURI) from 1,293 general practitioner practices between January 2020 and November 2021. AURI patients were matched 1:1 with COVID-19 patients using propensity scores based on sex, age, index quarter, health insurance type, the number of doctor visits, and comorbidities associated with dementia risk. Incidence rates of newly-diagnosed dementia were calculated using the person-years method. Poisson regression models were used to compute the incidence rate ratios (IRR). Results: The present study included 8,129 matched pairs (mean age 75.1 years, 58.9% females). After 12 months of follow-up, 1.84% of the COVID-19 patients and 1.78% of the AURI patients had been diagnosed with dementia. The Poisson regression model resulted in an IRR of 1.05 (95% CI: 0.85–1.29). Conclusion: This study did not find any association between COVID-19 infection and one-year dementia incidence after controlling for all common risk factors for dementia. Because dementia is a progressive disease, which can be difficult to diagnose, a longer follow-up period might offer a better insight into a possible association between COVID-19 infection and an increased incidence of dementia cases in the future.

Anisa J. Marshall, Aimee Gaubert, Arunima Kapoor, Alick Tan, Elissa McIntosh, Jung Yun Jang, Belinda Yew, Jean K. Ho, Anna E. Blanken, Shubir Dutt, Isabel J. Sible, Yanrong Li, Kathleen Rodgers, Daniel A. Nation
Blood-Derived Progenitor Cells Are Depleted in Older Adults with Cognitive Impairment: A Role for Vascular Resilience?
Abstract: Background: Depletion of blood-derived progenitor cells, including so called “early endothelial progenitor cells”, has been observed in individuals with early stage Alzheimer’s disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. Objective: To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. Methods: We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro. Neuropsychological testing was administered to all participants. Results: Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. Conclusion: These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults.

Jialing Fan*, Zhibao Zhu*, Yaojing Chen, Caishui Yang, Xin Li, Kewei Chen, Xiaochun Chen, Zhanjun Zhang (Handling Associate Editor: Liyong Wu) *These authors contributed equally to this work.
SORL1 rs1699102 Moderates the Effect of Sex on Language Network
Abstract: Background: Language ability differs between the sexes. However, it is unclear how this sex difference is moderated by genetic factors and how the brain interacts with genetics to support this specific language capacity. Previous studies have demonstrated that the sorting protein-related receptor (SORL1) polymorphism influences cognitive function and brain structure differently in males and females and is associated with Alzheimer's disease risk. Objective: The aim of this study was to investigate the effects of sex and the SORL1 rs1699102 (CC versus T carriers) genotype on language. Methods: 103 non-demented Chinese older adults from Beijing Aging Brain Rejuvenation Initiative (BABRI) database were included in this study. Participants completed language tests, T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional MRI. Language test performance, gray matter volume, and network connections were compared between genotype and sex groups. Results: The rs1699102 polymorphism moderated the effects of sex on language performance, with the female having reversed language advantages in T carriers. The T allele carriers had lower gray matter volume in the left precentral gyrus. The effect of sex on language network connections was moderated by rs1699102; male CC homozygotes and female T carriers had higher internetwork connections, which were negatively correlated with language performance. Conclusion: These results suggest that SORL1 moderates the effects of sex on language, with T being a risk allele, especially in females. Our findings underscore the importance of considering the influence of genetic factors when examining sex effects.

Yu Hirota*, Yasufumi Sakakibara*, Kimi Takei, Risa Nishijima, Michiko Sekiya, Koichi M. Iijima (Handling Associate Editor: Ikuo Tooyama) aThese authors contributed equally to this work.
Alzheimer’s Disease-Related Phospho-Tau181 Signals Are Localized to Demyelinated Axons of Parvalbumin-Positive GABAergic Interneurons in an App Knock-In Mouse Model of Amyloid-β Pathology
Abstract: Background: The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer’s disease (AD). Increased p-tau181 levels correlate well with amyloid-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF). However, from which neuronal subtype(s) these p-tau181-positive axons originate remains elusive. Objective: The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with p-tau181-positive axons by immunohistochemical analysis of AppNLGF mice brains. Methods: Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ pathology were analyzed. The density of these axons was also compared. Results: Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in AppNLGF mice. Conclusion: This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of Aβ pathology.

Jing Cheng, Huancheng Zheng, Chenyu Liu, Jiabin Jin, Zhenkai Xing, Yili Wu
Age-Associated UBE2O Reduction Promotes Neuronal Death in Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly. Ubiquitin proteasome system (UPS) is critical for protein homeostasis, while the functional decline of UPS with age contributes to the pathogenesis of AD. Ubiquitin-conjugating enzyme E2O (UBE2O), an E2-E3 hybrid enzyme, is a major component of UPS. However, its role in AD pathogenesis has not been fully defined. Objective: We aimed to identify the age-associated expression of UBE2O and its role AD pathogenesis. Methods: Western blot analysis were used to assess expression of UBE2O in organs/tissues and cell lines. Immunofluorescence staining was performed to examine the cellular distribution of UBE2O. Neuronal death was determined by the activity of lactate dehydrogenase. Results: UBE2O is highly expressed in the cortex and hippocampus. It is predominantly expressed in neurons but not in glial cells. The peak expression of UBE2O is at postnatal day 17 and 14 in the cortex and hippocampus, respectively. Moreover, its expression is gradually reduced with age. Importantly, UBE2O is significantly reduced in both cortex and hippocampus of AD mice. Consistently, overexpression of amyloid-β protein precursor (AβPP) with a pathogenic mutation (AβPPswe) for AD reduces the expression of UBE2O and promotes neuronal death, while increased expression of UBE2O rescues AβPPswe-induced neuronal death. Conclusion: Our study indicates that age-associated reduction of UBE2O may facilitates neuronal death in AD, while increasing UBE2O expression or activity may be a potential approach for AD treatment by inhibiting neuronal death.

Lenique K.L. Huggins, Se Hee Min, Samantha Kaplan, Jingkai Wei, Kathleen Welsh-Bohmer, Hanzhang Xu
Meta-Analysis of Variations in Association between APOE ε4 and Alzheimer’s Disease and Related Dementias Across Hispanic Regions of Origin
Abstract: Background: Emerging research has shown racial and ethnic variations in the magnitude of association between the apolipoprotein ε4 (APOE ε4) allele and the risk of developing Alzheimer’s disease and related dementias (ADRD). Studies researching this association among Hispanic groups within and outside of the United States have produced inconsistent results. Objective: To examine the association between the APOE ε4 allele and the risk of developing ADRD in global Hispanic populations from different ethnic regions of origin. Methods: PubMed, Embase, Scopus, and PsycInfo were searched for studies relating to Hispanic/Latin American origin, APOE ε4, and ADRD. Odds ratios (OR) of ADRD risk for individuals with APOE ε4 versus those without APOE ε4 were extracted and calculated using random effects analysis. Results: 20 eligible studies represented Caribbean Hispanic, Mexican, South American, Spanish, and Cuban groups. Overall, APOE ε4 was significantly associated with increased risk of ADRD (Odds Ratio [OR] 3.80, 95% CI: 2.38-6.07). The association was only significant in the South American (OR: 4.61, 95% CI: 2.74 – 7.75) subgroup. Conclusion: There was an association between APOE ε4 and increased ADRD risk for the South American subgroup. The strength of this association varied across Hispanic subgroups. Data is limited with more studies especially needed for adjusted analysis on Spanish, Central American, Cuban Hispanic, and Caribbean Hispanic groups. Results suggest additional environmental or genetic risk factors are associated with ethnic variations.

Chunyan Jiang, Yongxiang Wang, Yi Dong, Rui Liu, Lin Song, Shanshan Wang, Zhe Xu, Sijie Niu, Yifei Ren, Xiaodong Han, Mingqing Zhao, Jiafeng Wang, Xiaohui Li, Lin Cong, Tingting Hou, Qinghua Zhang, Yifeng Du, Chengxuan Qiu
Associations of Microvascular Dysfunction with Mild Cognitive Impairment and Cognitive Function Among Rural-Dwelling Older Adults in China
Abstract: Background: Microvascular dysfunction (MVD) may contribute to cognitive impairment and Alzheimer’s disease, but evidence is limited. Objective: To investigate the association of composite and organ-specific MVD burden with mild cognitive impairment (MCI) and cognition among rural-dwelling Chinese older adults. Methods: In this population-based cross-sectional study, we assessed MVD makers using optical coherence tomographic angiography for retinal microvasculature features, brain magnetic resonance imaging scans for cerebral small vessel disease (CSVD), and serum biomarkers for MVD. A composite MVD score was generated from the aforementioned organ-specific parameters. We used a neuropsychological test battery to assess memory, verbal fluency, attention, executive function, and global cognitive function. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were diagnosed following the Petersen’s criteria. Data was analyzed with the linear and logistic regression models. Results: Of the 274 dementia-free participants (age≥65 years), 56 were diagnosed with MCI, including 47 with aMCI and 9 with naMCI. A composite MVD score was statistically significantly associated with an odds ratio (OR) of 2.70 (95% confidence interval 1.12−6.53) for MCI and β-coefficient of -0.29 (-0.48−-0.10) for global cognitive score after adjustment for socio-demographics, lifestyle factors, APOE genotype, the Geriatric Depression Scale score, serum inflammatory biomarkers, and cardiovascular comorbidity. A composite score of retinal microvascular morphology was associated with a multivariable-adjusted OR of 1.72 (1.09−2.73) for MCI and multivariable-adjusted β-coefficient of -0.11 (-0.22−-0.01) for global cognitive score. A composite CSVD score was associated with a lower global cognitive score (β=-0.10; -0.17−-0.02). Conclusion: Microvascular dysfunction, especially in the brain and retina, is associated with MCI and poor cognitive function among rural-dwelling older adults.

Luca Sacchi, Valeria Elisa Contarino, Silvia Siggillino, Tiziana Carandini, Giorgio Giulio Fumagalli, Anna Margherita Pietroboni, Marina Arcaro, Chiara Fenoglio, Eva Orunesu, Massimo Castellani, Silvia Casale, Giorgio Conte, Chunlei Liu, Fabio Triulzi, Daniela Galimberti, Elio Scarpini, Andrea Arighi (Handling Associate Editor: Marco Bozzali)
Banks of the Superior Temporal Sulcus in Alzheimer’s Disease: A Pilot Quantitative Susceptibility Mapping Study
Abstract: Background: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer’s disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). Objective: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. Methods: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n=19) and non-AD (n=15) groups according to their clinical profile, CSF (Aβ42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. Results: QSM in left BANKSSTS was significantly different among groups (p=0.003, H=11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aβ42 (rho -0.55, p=0.005), Aβ42/40 (rho -0.66, p<0.001), pTau (rho 0.63, p<0.001), tTau (rho 0.56, p=0.005), tTau/Aβ42 (rho 0.68, p<0.001) and pTau/Aβ42 (rho 0.71, p<0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC=0.80, CI95% [0.66-0.93]). Higher QSM values were independent predictors of Aβ42 (B=0.63, p=0.032), Aβ42/40 (B=0.81, p=0.028), pTau (B=0.96, p=0.046), tTau (B=0.55, p=0.027), and tTau/Aβ42 (B=1.13, p=0.042) positivity. Conclusion: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

Alana V. Beadell*, Zhou Zhang*, Ana W. Capuano, David A. Bennett, Chuan He, Wei Zhang, Zoe Arvanitakis (Handling Associate Editor: Jose Luchsinger) *These authors contributed equally.
Genome-Wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes Mellitus and Alzheimer’s Disease
Abstract: Background: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer’s disease dementia may provide insights into much needed dementia therapeutics. Objective: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC). Methods: We obtained clinical samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer’s disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls). Results: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUC=91.8%; 95% CI, 82.9-100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUC=87.9%; 95% CI, 77.5-98.3%). Conclusion: We demonstrate in this small sample the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes.

Jianfeng Wu, Yi Su, Yanxi Chen, Wenhui Zhu, Eric M. Reiman, Richard J. Caselli, Kewei Chen, Paul M. Thompson, Junwen Wang, Yalin Wang, Alzheimer’s Disease Neuroimaging Initiative
A Surface-Based Federated Chow Test Model for Integrating APOE Status, Tau Deposition Measure, and Hippocampal Surface Morphometry
Abstract: Background: Alzheimer’s disease (AD) is the most common type of age-related dementia, affecting 6.2 million people aged 65 or older according to CDC data. It is commonly agreed that discovering an effective AD diagnosis biomarker could have enormous public health benefits, potentially preventing or delaying up to 40% of dementia cases. Tau neurofibrillary tangles are the primary driver of downstream neurodegeneration and subsequent cognitive impairment in AD, resulting in structural deformations such as hippocampal atrophy that can be observed in magnetic resonance imaging (MRI) scans. Objective: To build a surface-based model to 1) detect differences between APOE subgroups in patterns of tau deposition and hippocampal atrophy, and 2) use the extracted surface-based features to predict cognitive decline. Methods: Using data obtained from different institutions, we develop a surface-based federated Chow test model to study the synergistic effects of APOE, a previously reported significant risk factor of AD, and tau on hippocampal surface morphometry. Results: We illustrate that the APOE-specific morphometry features correlate with AD progression and better predict future AD conversion than other MRI biomarkers. For example, a strong association between atrophy and abnormal tau was identified in hippocampal subregion cornu ammonis 1 (CA1 subfield) and subiculum in e4 homozygote cohort. Conclusion: Our model allows for identifying MRI biomarkers for AD and cognitive decline prediction and may uncover a corner of the neural mechanism of the influence of APOE and tau deposition on hippocampal morphology.

Sergi Borrego-Écija*, Nuria Montagut*, Pablo Martín-Trias, Lídia Vaqué-Alcázar, Ignacio Illán-Gala, Mircea Balasa, Albert Lladó, Jordi Casanova-Mollà, Nuria Bargalló, Josep Valls-Solé, Alberto Lleó, David Bartrés-Faz, Raquel Sánchez-Valle *These authors contributed equally to this work.
Multifocal Transcranial Direct Current Stimulation in Primary Progressive Aphasia Does Not Provide a Clinical Benefit Over Speech Therapy
Abstract: Background: Primary progressive aphasia (PPA) is a group of neurodegenerative disorders including Alzheimer's disease and frontotemporal dementia characterized by language deterioration. Transcranial direct current stimulation (tDCS) is a non-invasive intervention for brain dysfunction. Objective: To evaluate the tolerability and efficacy of tDCS combined with speech therapy in the three variants of PPA. We evaluate changes in fMRI activity in a subset of patients. Methods: Double-blinded, randomized, cross-over, and sham-controlled tDCS study. 15 patients with PPA were included. Each patient underwent two interventions: a) speech therapy + active tDCS and b) speech therapy + sham tDCS stimulation. A multifocal strategy with anodes placed in the left frontal and parietal regions was used to stimulate the entire language network. Efficacy was evaluated by comparing the results of two independent sets of neuropsychological assessments administered at baseline, immediately after the intervention, and at 1 month and 3 months after the intervention. In a subsample, fMRI scanning was performed before and after each intervention. Results: The interventions were well tolerated. Participants in both arms showed clinical improvement, but no differences were found between active and sham tDCS interventions in any of the evaluations. There were trends toward better outcomes in the active tDCS group for semantic association and reading skills. fMRI identified an activity increase in the right frontal medial cortex and the bilateral paracingulate gyrus after the active tDCS intervention. Conclusion: We did not find differences between active and sham tDCS stimulation in clinical scores of language function in PPA patients.

Viha Vig, Itika Garg, Fatima Tuz-Zahra, Jia Xu, Yorghos Tripodis, Raymond Nicks, Weiming Xia, Victor E. Alvarez, Michael L. Alosco, Thor D. Stein*, Manju L. Subramanian* *These authors contributed equally to this study.
Vitreous Humor Biomarkers Reflect Pathological Changes in the Brain for Alzheimer’s Disease and Chronic Traumatic Encephalopathy
Abstract: Background: Patients with eye disease have an increased risk for developing neurodegenerative disease. Neurodegenerative proteins can be measured in the eye; however, correlations between biomarker levels in eye fluid and neuropathological diagnoses have not been established. Objective: This exploratory, retrospective study examined vitreous humor from 41 postmortem eyes and brain tissue with neuropathological diagnoses of Alzheimer’s disease (AD, n=7), chronic traumatic encephalopathy (CTE, n=15), both AD + CTE (n=10), and without significant neuropathology (controls, n=9). Methods: Protein biomarkers i.e., amyloid-β (Aβ40,42), total tau (tTau), phosphorylated tau (pTau181, 231), neurofilament light chain (NfL), and eotaxin-1 were quantitatively measured by immunoassay. Non-parametric tests were used to compare vitreous biomarker levels between groups. Spearman’s rank correlation tests were used to correlate biomarker levels in vitreous and cortical tissue. The level of significance was set to α=0.10. Results: In pairwise comparisons, tTau levels were significantly increased in AD and CTE groups versus controls (p=0.08 for both) as well as AD versus AD+CTE group and CTE versus AD+CTE group (p=0.049 for both). Vitreous NfL levels were significantly increased in low CTE (Stage I/II) versus no CTE (p=0.096) and in low CTE versus high CTE stage (p=0.03). Vitreous and cortical tissue levels of pTau 231 (p=0.02, r=0.38) and t-Tau (p=0.04, r=-0.34) were significantly correlated. Conclusion: The postmortem vitreous humor biomarker levels significantly correlate with AD and CTE pathology in corresponding brains, while vitreous NfL was correlated with the CTE staging. This exploratory study indicates that biomarkers in the vitreous humor may serve as a proxy for neuropathological disease.