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Background: Limited research has explored the effect of cardiovascular risk and amyloid interplay on cognitive decline in East Asians., Methods: Vascular burden was quantified using Framingham's General Cardiovascular Risk Score (FRS) in 526 Korean Brain Aging Study (KBASE) participants. Cognitive differences in groups stratified by FRS and amyloid positivity were assessed at baseline and longitudinally., Results: Baseline analyses revealed that amyloid-negative (Aβ-) cognitively normal (CN) individuals with high FRS had lower cognition compared to Aβ- CN individuals with low FRS (p < 0.0001). Longitudinally, amyloid pathology predominantly drove cognitive decline, while FRS alone had negligible effects on cognition in CN and mild cognitive impairment (MCI) groups., Conclusion: Our findings indicate that managing vascular risk may be crucial in preserving cognition in Aβ- individuals early on and before the clinical manifestation of dementia. Within the CN and MCI groups, irrespective of FRS status, amyloid-positive individuals had worse cognitive performance than Aβ- individuals., Highlights: Vascular risk significantly affects cognition in amyloid-negative older Koreans. Amyloid-negative CN older adults with high vascular risk had lower baseline cognition. Amyloid pathology drives cognitive decline in CN and MCI, regardless of vascular risk. The study underscores the impact of vascular health on the AD disease spectrum., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin + inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb + and Vip + inhibitory neuron subtypes. These findings were replicated in other major AD studies., (© 2024. The Author(s).)

This study protocol describes the development of the first instrument of functional communication for people living with primary progressive aphasia (PPA), with future applications to other progressive conditions, with expert validation, item-level reliability analyses, input from partners in research, and outcomes. Progressive conditions like PPA require monitoring, and as such, re-assessment. Re-assessment poses the high risk of being burdensome, destructive, and of little use to the patient. As such, there is a significant need to establish a validated and reliable measure that (1) poses minimal patient burden and (2) captures communication ability in a strengths-based manner for both clinical and research purposes. A strengths-based approach to assessment is widely recognized as the optimal way to promote patient autonomy, minimize harm, and implement functional treatment protocols and strategies. To date, there are no strengths-based assessment tools that were developed for people living with PPA nor ways to efficiently document functional communication performance. This study protocol outlines our work to address this gap in clinical practice and research., Competing Interests: The authors have declared that no competing interests exist. The experimental approach described in this manuscript is supported by a 2024-2025 University of Washington Alzheimer’s Disease Research Center Development Project Award (JG). This work was also supported by the National Institute on Aging (U24 AG074855: JG & PKC; P30 AG066509: KDR)., (Copyright: © 2024 Gallée et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Changes in sleep, physical activity and mental health were observed in older adults during early stages of the COVID-19 pandemic. Here we describe effects of the COVID-19 pandemic on older adult mental health, wellbeing, and lifestyle behaviors and explore predictors of better mid-pandemic mental health and wellbeing., Methods: Participants in the Adult Changes in Thought study completed measures of lifestyle behaviors (e.g., sleep, physical activity) and mental health and wellbeing both pre-pandemic during regular study visits and mid-pandemic via a one-time survey. We used paired t-tests to compare differences in these measures pre- vs. mid-pandemic. Using multivariate linear regression, we further explored demographic, health, and lifestyle predictors of pandemic depressive symptoms, social support, and fatigue. We additionally qualitatively coded free text data from the mid-pandemic survey for related comments., Results: Participants (N = 896) reported significant changes in mental health and lifestyle behaviors at pre-pandemic vs. mid-pandemic measurements (p < 0.0001). Qualitative findings supported these behavioral and wellbeing changes. Being male, never smoking, and lower pre-pandemic computer time and sleep disturbance were significantly associated with lower pandemic depressive symptoms. Being partnered, female, never smoking, and lower pre-pandemic sleep disturbance were associated with higher pandemic social support. Pre-pandemic employment, more walking, less computer time, and less sleep disturbance were associated with less pandemic fatigue. Participant comments supported these quantitative findings, highlighting gender differences in pandemic mental health, changes in computer usage and physical activity during the pandemic, the value of spousal social support, and links between sleep disturbance and mental health and wellbeing. Qualitative findings also revealed additional factors, such as stresses from personal and family health situations and the country's concurrent political environment, that impacted mental health and wellbeing., Conclusions: Several demographic, health, and lifestyle behaviors appeared to buffer the effects of the COVID-19 pandemic and may be key sources of resilience. Interventions and public health measures targeting men and unpartnered individuals could promote social support resilience, and intervening on modifiable behaviors like sleep quality, physical activity and sedentary activities like computer time may promote resilience to fatigue and depressive symptoms during future community stressor events. Further research into these relationships is warranted., (© 2024. The Author(s).)

Aim: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes., Materials and Methods: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score., Results: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores., Conclusions: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes., (© 2024 John Wiley & Sons Ltd.)

Throughout an organism's life, a multitude of complex and interdependent biological systems transition through biophysical processes that serve as indicators of the underlying biological states. Inferring these latent, unobserved states is a goal of modern biology and neuroscience. However, in many experimental setups, we can at best obtain discrete snapshots of the system at different times and for different individuals. This challenge is particularly relevant in the study of Alzheimer's Disease (AD) progression, where we observe the aggregation of pathology in brain donors, but the underlying disease state is unknown. This paper proposes a biophysically motivated Bayesian framework (B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics), where the disease state is modeled and continuously inferred from observed quantifications of multiple AD pathological proteins. Inspired by biophysical models, we describe pathological burden as an exponential process. The progression of AD is modeled by assigning a latent score, termed pseudotime, to each pathological state, creating a pseudotemporal order of donors based on their pathological burden. We study the theoretical properties of the model using linearization to reveal convergence and identifiability properties. We provide Markov chain Monte Carlo estimation algorithms, illustrating the effectiveness of our approach with multiple simulation studies across various data conditions. Applying this methodology to data from the Seattle Alzheimer's Disease Brain Cell Atlas, we infer the pseudotime ordering of donors. Finally, we analyze the information within each pathological feature to refine the model, focusing on the most informative pathologies. This framework lays the groundwork for continuous pseudotime modeling in the analysis of neurodegenerative diseases.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD., Competing Interests: DY, BH, BD, SM, BK, YD, LD, YW, AN, AK, YZ, HK, SJ, CC, TH, PC, CE, QL No competing interests declared, (© 2023, Yan, Hu et al.)

Objective: To determine the impact of type 2 diabetes and glycated hemoglobin (HbA1c) levels within the recommended target range according to the Japan Diabetes Society/Japan Geriatrics Society Joint Committee on mortality in older adults with cognitive impairment., Research Design and Methods: This retrospective cohort study included 1,528 and 468 patients aged ≥65 years without and with type 2 diabetes, respectively, who were visiting a memory clinic. The 468 patients with type 2 diabetes were divided into three groups (within, above, and below the target range) based on their HbA1c levels, cognitive function, ability to perform activities of daily living, and medications associated with a high risk of hypoglycemia. The impact of diabetes and HbA1c levels on mortality was evaluated using Cox proportional hazards models., Results: Over a median follow-up period of 3.8 years, 353 patients (17.7%) died. Compared with individuals without type 2 diabetes, HbA1c levels above (hazard ratio [HR] 1.70, 95% CI 1.08-2.69) and below (HR 2.15, 95% CI 1.33-3.48) the target range were associated with a higher risk of death; however, HbA1c levels within the target range were not (HR 1.02, 95% CI 0.77-1.36)., Conclusions: HbA1c levels above and below the target range were associated with a higher risk of mortality, whereas patients with HbA1c levels within the target range did not exhibit a higher risk of mortality than individuals without type 2 diabetes. These results provide empirical support for the current target ranges among older adults with cognitive impairment., (© 2024 by the American Diabetes Association.)

Introduction: We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups., Methods: We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory., Results: There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10 -10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group., Discussion: MRI findings differ across cognitively defined AD subgroups., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults., Methods: Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated., Results: The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating μVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating μVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7)., Discussion: Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline., Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts., Results: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits., Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline., Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear., Methods: We conducted the largest sex-aware genetic study on late-life memory to date (N males  = 11,942; N females  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants., Results: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits., Discussion: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory., Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994., Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer's disease generalized to all older adults in the Seattle Metropolitan Region., Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer's disease incidence. Cox proportional hazards models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights., Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer's disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT., Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights.

Background: Conflicting research on retinal biomarkers of Alzheimer's disease and related dementias (AD/ADRD) is likely related to limited sample sizes, study design, and protocol differences., Objective: The prospective Eye Adult Changes in Thought (Eye ACT) seeks to address these gaps., Methods: Eye ACT participants are recruited from ACT, an ongoing cohort of dementia-free, older adults followed biennially until AD/ADRD, and undergo visual function and retinal imaging assessment either in clinic or at home., Results: 330 participants were recruited as of 03/2023. Compared to ACT participants not in Eye ACT (N = 1868), Eye ACT participants (N = 330) are younger (mean age: 70.3 versus 71.2, p = 0.014), newer to ACT (median ACT visits since baseline: 3 versus 4, p < 0.001), have more years of education (17.7 versus 16.2, p < 0.001) and had lower rates of visual impairment (12% versus 22%, p < 0.001). Compared to those seen in clinic (N = 300), Eye ACT participants seen at home (N = 30) are older (77.2 versus 74.9, p = 0.015), more frequently female (60% versus 49%, p = 0.026), and have significantly worse visual acuity (71.1 versus 78.9 Early Treatment Diabetic Retinopathy Study letters, p < 0.001) and contrast sensitivity (-1.9 versus -2.1 mean log units at 3 cycles per degree, p = 0.002). Cognitive scores and retinal imaging measurements are similar between the two groups., Conclusions: Participants assessed at home had significantly worse visual function than those seen in clinic. By including these participants, Eye ACT provides a unique longitudinal cohort for evaluating potential retinal biomarkers of dementia.

Background: While epidemiologic evidence links higher levels of exposure to fine particulate matter (PM 2.5 ) to decreased cognitive function, fewer studies have investigated links with traffic-related air pollution (TRAP), and none have examined ultrafine particles (UFP, ≤100 nm) and late-life dementia incidence., Objective: To evaluate associations between TRAP exposures (UFP, black carbon [BC], and nitrogen dioxide [NO 2 ]) and late-life dementia incidence., Methods: We ascertained dementia incidence in the Seattle-based Adult Changes in Thought (ACT) prospective cohort study (beginning in 1994) and assessed ten-year average TRAP exposures for each participant based on prediction models derived from an extensive mobile monitoring campaign. We applied Cox proportional hazards models to investigate TRAP exposure and dementia incidence using age as the time axis and further adjusting for sex, self-reported race, calendar year, education, socioeconomic status, PM 2.5 , and APOE genotype. We ran sensitivity analyses where we did not adjust for PM 2.5 and other sensitivity and secondary analyses where we adjusted for multiple pollutants, applied alternative exposure models (including total and size-specific UFP), modified the adjustment covariates, used calendar year as the time axis, assessed different exposure periods, dementia subtypes, and others., Results: We identified 1,041 incident all-cause dementia cases in 4,283 participants over 37,102 person-years of follow-up. We did not find evidence of a greater hazard of late-life dementia incidence with elevated levels of long-term TRAP exposures. The estimated hazard ratio of all-cause dementia was 0.98 (95 % CI: 0.92-1.05) for every 2000 pt/cm 3 increment in UFP, 0.95 (0.89-1.01) for every 100 ng/m 3 increment in BC, and 0.96 (0.91-1.02) for every 2 ppb increment in NO 2 . These findings were consistent across sensitivity and secondary analyses., Discussion: We did not find evidence of a greater hazard of late-life dementia risk with elevated long-term TRAP exposures in this population-based prospective cohort study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Repeated measure data design has been used extensively in a wide range of fields, such as brain aging or developmental psychology, to answer important research questions exploring relationships between trajectory of change and external variables. In many cases, such data may be collected from multiple study cohorts and harmonized, with the intention of gaining higher statistical power and enhanced external validity. When psychological constructs are measured using survey scales, a fundamental psychometric challenge for data harmonization is to create commensurate measures for the constructs of interest across studies. Traditional analysis may fit a unidimensional item response theory model to data from one time point and one cohort to obtain item parameters and fix the same parameters in subsequent analyses. Such a simplified approach ignores item residual dependencies in the repeated measure design on one hand, and on the other hand, it does not exploit accumulated information from different cohorts. Instead, two alternative approaches should serve such data designs much better: an integrative approach using multiple-group two-tier model via concurrent calibration, and if such calibration fails to converge, a Bayesian sequential calibration approach that uses informative priors on common items to establish the scale. Both approaches use a Markov chain Monte Carlo algorithm that handles computational complexity well. Through a simulation study and an empirical study using Alzheimer's diseases neuroimage initiative cognitive battery data (i.e., language and executive functioning), we conclude that latent change scores obtained from these two alternative approaches are more precisely recovered. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction: Alzheimer's disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity., Methods: We conducted co-expression network analysis and identified gene sets (modules) that were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits including neuritic plaques (NPs) and neurofibrillary tangles (NFTs). We computed the module-based PRSs (mbPRSs) for each module and tested associations with mbPRSs for cognitive test scores, cognitively defined AD subgroups, and brain imaging data., Results: Of the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning, respectively. They matched clinical subtypes and brain atrophy at specific regions., Discussion: Our findings demonstrate that polygenic profiling based on co-expressed gene sets can explain heterogeneity in AD patients, enabling genetically informed patient stratification and precision medicine in AD., Highlights: Co-expression gene-network analysis in Alzheimer's disease (AD) brains identified gene sets (modules) associated with AD heterogeneity. AD-associated modules were selected when genes in each module were enriched for neuritic plaques and neurofibrillary tangles. Polygenic risk scores from two selected modules were linked to the matching cognitively defined AD subgroups (language and visuospatial subgroups). Polygenic risk scores from the two modules were associated with cognitive performance in language and visuospatial domains and the associations were confirmed in regional-specific brain atrophy data., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Identification of novel risk factors for dementia in older adults could facilitate development of methods to identify patients most at risk and improve their cognitive outcomes. We aimed to determine whether lower appendicular lean mass (ALM), assessed by dual-energy x-ray absorptiometry (DXA), and lower grip strength are associated with a greater likelihood of incident dementia among older adults in the Health Aging and Body Composition Study (Health ABC)., Methods: Health ABC data from 1997 to 2008 were analyzed (n = 2 704). Baseline ALM to body mass index (BMI) ratio (ALMBMI) was assessed by DXA. Baseline grip strength was assessed by hand-held dynamometry. Incident dementia diagnosis was defined as either (i) dementia-related hospitalization plus a Modified Mini-Mental State Examination (3MS) score of ≤ 90; or (ii) record of prescription for anti-dementia medication; or (iii) decline of at least 1.5 SDs on the 3MS score compared to baseline. Cox proportional hazard models estimated associations of ALMBMI and grip strength with incident dementia over follow-up with and without adjusting for covariates, stratified by sex., Results: Among older men, each standard deviation decrement in ALMBMI (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.07, 1.65) or grip strength (aHR 1.22; 95% CI: 1.06, 1.41) was associated with increased likelihood of incident dementia., Conclusions: Lower ALMBMI and grip strength may be important risk factors for the development of dementia among older men. How these factors may belong to a causal pathway of dementia must be elucidated in future work., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10 -14 ; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen., (© 2023. The Author(s).)

Background: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH., Methods: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations., Results: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation., Conclusions: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population., Competing Interests: KMJ was employed by Bristol-Myers Squibb during the drafting of this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors report no conflicts of interest to disclose., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Importance: High visit-to-visit blood pressure variability (BPV) in late life may reflect increased dementia risk better than mean systolic blood pressure (SBP). Evidence from midlife to late life could be crucial to understanding this association., Objective: To determine whether visit-to-visit BPV at different ages was differentially associated with lifetime incident dementia risk in community-dwelling individuals., Design, Setting, and Participants: This cohort study analyzed data from the Adult Changes in Thought (ACT) study, an ongoing population-based prospective cohort study in the US. Participants were 65 years or older at enrollment, community-dwelling, and without dementia. The study focused on a subset of deceased participants with brain autopsy data and whose midlife to late-life blood pressure data were obtained from Kaiser Permanente Washington medical archives and collected as part of the postmortem brain donation program. In the ACT study, participants underwent biennial medical assessments, including cognitive screening. Data were collected from 1994 (ACT study enrollment) through November 2019 (data set freeze). Data analysis was performed between March 2020 and September 2023., Exposures: Visit-by-visit BPV at ages 60, 70, 80, and 90 years, calculated using the coefficient of variation of year-by-year SBP measurements over the preceding 10 years., Main Outcomes and Measures: All-cause dementia, which was adjudicated by a multidisciplinary outcome adjudication committee., Results: A total of 820 participants (mean [SD] age at enrollment, 77.0 [6.7] years) were analyzed and included 476 females (58.0%). A mean (SD) of 28.4 (8.4) yearly SBP measurements were available over 31.5 (9.0) years. The mean (SD) follow-up time was 32.2 (9.1) years in 27 885 person-years from midlife to death. Of the participants, 372 (45.4%) developed dementia. The number of participants who were alive without dementia and had available data for analysis ranged from 280 of those aged 90 years to 702 of those aged 70 years. Higher BPV was not associated with higher lifetime dementia risk at age 60, 70, or 80 years. At age 90 years, BPV was associated with 35% higher dementia risk (hazard ratio [HR], 1.35; 95% CI, 1.02-1.79). Meta-regression of HRs calculated separately for each age (60-90 years) indicated that associations of high BPV with higher dementia risk were present only at older ages, whereas the association of SBP with dementia gradually shifted direction linearly from being incrementally to inversely associated with older ages., Conclusions and Relevance: In this cohort study, high BPV indicated increased lifetime dementia risk in late life but not in midlife. This result suggests that high BPV may indicate increased dementia risk in older age but might be less viable as a midlife dementia prevention target.

Background: Tobacco smoking increases frailty risk among the general population and is common among people with HIV (PWH) who experience higher rates of frailty at younger ages than the general population., Methods: We identified 8608 PWH across 6 Centers for AIDS Research Network of Integrated Clinical Systems sites who completed ≥2 patient-reported outcome assessments, including a frailty phenotype measuring unintentional weight loss, poor mobility, fatigue, and inactivity, and scored 0-4. Smoking was measured as baseline pack-years and time-updated never, former, or current use with cigarettes/day. We used Cox models to associate smoking with risk of incident frailty (score ≥3) and deterioration (frailty score increase by ≥2 points), adjusted for demographics, antiretroviral medication, and time-updated CD4 count., Results: The mean follow-up of PWH was 5.3 years (median: 5.0), the mean age at baseline was 45 years, 15% were female, and 52% were non-White. At baseline, 60% reported current or former smoking. Current (HR: 1.79; 95% confidence interval: 1.54 to 2.08) and former (HR: 1.31; 95% confidence interval: 1.12 to 1.53) smoking were associated with higher incident frailty risk, as were higher pack-years. Current smoking (among younger PWH) and pack-years, but not former smoking, were associated with higher risk of deterioration., Conclusions: Among PWH, smoking status and duration are associated with incident and worsening frailty., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well-characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia-free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross-sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all-cause and AD dementia during up to 20 years of follow-up were tested. APOE genotype-stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF-R, TWEAK, CCL19, IL-17C, MCP-4, and TGF-alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all-cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Introduction: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology., Methods: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries., Results: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits., Discussion: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range., Highlights: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS., (© 2023 the Alzheimer's Association.)

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele., Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition., Design, Setting, and Participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022., Main Outcomes and Measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons., Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals., Conclusions and Relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

Background: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking. We used polygenic risk scores (PRS) to explore genetic mechanisms of T2MI compared to T1MI in PWH., Methods: We derived 115 PRS for MI-related traits in 9541 PWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort with adjudicated T1MI and T2MI. We applied multivariate logistic regression analyses to determine the association with T1MI and T2MI. Based on initial findings, we performed gene set enrichment analysis of the top variants composing PRS associated with T2MI., Results: We found that T1MI was strongly associated with PRS for cardiovascular disease, lipid profiles, and metabolic traits. In contrast, PRS for alcohol dependence and cholecystitis, significantly enriched in energy metabolism pathways, were predictive of T2MI risk. The association remained after the adjustment for actual alcohol consumption., Conclusions: We demonstrate distinct genetic traits associated with T1MI and T2MI among PWH further highlighting their etiological differences and supporting the role of energy regulation in T2MI pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10 -5 ), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD., (© 2023. The Author(s).)

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes., Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software., Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10 -9 ). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10 -8 ) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10 -8 ). GRN (rs5848, P = 4.21 × 10 -8 ) and PURG (rs117523305, P = 1.73 × 10 -8 ) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10 -8 ) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10 -9 ) and PTPRD (rs145989094, P = 8.34 × 10 -9 ) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10 -8 ) and PTPRD (rs145989094, P = 3.85 × 10 -8 ) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD., Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias., (© 2023. The Author(s).)

The role of socioeconomic status (SES) across the life course in late-life cognition is unclear. We tested the hypotheses that: 1) High SES in childhood, young adulthood, midlife, and late life have independent causal effects on higher cognition level and slower cognitive decline; 2) Compared with stable low SES (referent), stable high SES has the largest estimated effect for higher cognition level and slower decline among life-course SES combinations. The Rush Memory and Aging Project enrolled 1,940 dementia-free older adults in northeastern Illinois (1997-2018). We used inverse probability-weighted marginal structural models to estimate the joint and independent effect of each life-course SES on global and domain-specific cognition. A total of 1,746 participants had, on average, 6 years of follow-up. High SES at each life-course stage starting in young adulthood had a protective estimated effect on global and domain-specific cognition intercepts. Compared with consistently low SES, consistently high SES (β = 0.64, 95% confidence interval: 0.48, 0.93) and high SES beyond childhood (β = 0.64, 95% confidence interval: 0.47, 0.83) had the largest benefit for global cognition intercepts. None of the life-course SES measures influenced rate of global or domain-specific decline. Additional understanding of life-course SES components influencing cognitive level is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ethnographic research with cognitively impaired older adults can be challenging, in part because cognitive impairment raises questions about the ability to provide informed consent. Relying on proxy consent is a commonly used strategy, but often excludes people with dementia who lack close kin (de Medeiros, Girling, & Berlinger, 2022). In this paper, we describe how we have analyzed existing research data from a well-established and ongoing prospective cohort study, the Adult Changes in Thought Study, along with unstructured text from the medical records of participants who had no living spouse or adult children when they developed dementia, as a way of studying the circumstances, life trajectories, caregiving resources, and care needs of this vulnerable and difficult-to-research group. In this article, we detail this methodology, exploring what can and cannot be gleaned from it, what the ethical implications may be, and how and whether this type of research can be considered ethnographic. In conclusion, we argue that collaborative interdisciplinary research using existing, longitudinal research data and text from medical records deserves to be considered as a potentially useful addition to the ethnographic toolkit. We anticipate that this is a methodology that could be applied more broadly, and paired with more traditional ethnographic methods, might be one way to make research with this population more inclusive., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: To examine the circumstances and needs of older adults who were "kinless," defined as having no living spouse or children, when they developed dementia., Methods: We conducted a secondary analysis of information from the Adult Changes in Thought study. Among 848 participants diagnosed with dementia between 1994 and 2016, we identified 64 who had no living spouse or child at dementia onset. We then conducted a qualitative analysis of administrative documents pertaining to these participants: handwritten comments recorded after each study visit, and medical history documents containing clinical chart notes from participants' medical records., Results: In this community-dwelling cohort of older adults diagnosed with dementia, 8.4% were kinless at dementia onset. Participants in this sample had an average age of 87 years old, half lived alone, and one third lived with unrelated persons. Through inductive content analysis, we identified 4 themes that describe their circumstances and needs: (1) life trajectories, (2) caregiving resources, (3) care needs and gaps, and (4) turning points in caregiving arrangements., Discussion: Our qualitative analysis reveals that the life trajectories that led members of the analytic cohort to be kinless at dementia onset were quite varied. This research highlights the importance of nonfamily caregivers and participants' own roles as caregivers. Our findings suggest that clinicians and health systems may need to work with other parties to directly provide dementia caregiving support rather than rely on family, and address factors such as neighborhood affordability that particularly affect older adults who have limited family support., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear., Materials and Methods: We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC., Results: Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): -0.042 (-0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer's disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness., Conclusions: Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set., Method: Participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores., Results: Across all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial., Conclusion: Modern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Purpose: To investigate whether associations between diabetic retinopathy (DR) and dementia and Alzheimer's disease (AD) remain significant after controlling for several measures of diabetes severity., Design: Retrospective cohort study., Methods: Adult Changes in Thought (ACT) is a prospective cohort study of adults aged ≥65 years, randomly selected and recruited from the membership rolls of Kaiser Permanente Washington, who are dementia free at enrollment and followed biennially until incident dementia. The ACT participants were included in this study if they had type 2 diabetes mellitus at enrollment or developed it during follow-up, and data were collected through September, 2018 (3516 person-years of follow-up). Diabetes was defined by ≥ 2 diabetes medication fills in 1 year. Diagnosis of DR was based on International Classification of Diseases Ninth and Tenth Revision codes. Estimates of microalbuminuria, long-term glycemia, and renal function from longitudinal laboratory records were used as indicators of diabetes severity. Alzheimer's disease and dementia were diagnosed using research criteria at expert consensus meetings., Results: A total of 536 participants (median baseline age 75 [interquartile range 71-80], 54% women) met inclusion criteria. Significant associations between DR >5 years duration with dementia (hazard ratio 1.81 [95% CI 1.23, 2.65]) and AD (1.80 [1.15, 2.82]) were not altered by adjustment for estimates of microalbuminuria, long-term glycemia, and renal function (dementia: 1.69 [1.14, 2.50]; AD: 1.73 [1.10, 2.74])., Conclusions: Among people with type 2 diabetes, DR itself appears to be an important biomarker of dementia risk in addition to glycemia and renal complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Studies use different instruments to measure cognitirating cognitive tests permit direct comparisons of individuals across studies and pooling data for joint analyses., Method: We began our legacy item bank with data from the Adult Changes in Thought study ( n = 5,546), the Alzheimer's Disease Neuroimaging Initiative ( n = 3,016), the Rush Memory and Aging Project ( n = 2,163), and the Religious on such as the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Wechsler Memory Scale, and the Boston Naming Test. CocalibOrders Study ( n = 1,456). Our workflow begins with categorizing items administered in each study as indicators of memory, executive functioning, language, visuospatial functioning, or none of these domains. We use confirmatory factor analysis models with data from the most recent visit on the pooled sample across these four studies for cocalibration and derive item parameters for all items. Using these item parameters, we then estimate factor scores along with corresponding standard errors for each domain for each study. We added additional studies to our pipeline as available and focused on thorough consideration of candidate anchor items with identical content and administration methods across studies., Results: Prestatistical harmonization steps such qualitative and quantitative assessment of granular cognitive items and evaluating factor structure are important steps when trying to cocalibrate cognitive scores across studies. We have cocalibrated cognitive data and derived scores for four domains for 76,723 individuals across 10 studies., Conclusions: We have implemented a large-scale effort to harmonize and cocalibrate cognitive domain scores across multiple studies of cognitive aging. Scores on the same metric facilitate meta-analyses of cognitive outcomes across studies or the joint analysis of individual data across studies. Our systematic approach allows for cocalibration of additional studies as they become available and our growing item bank enables robust investigation of cognition in the context of aging and dementia. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies., Method: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies., Results: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change., Conclusions: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: To calibrate cognitive assessment data across multiple waves of the Framingham Heart Study (FHS), addressing study design considerations, ceiling effects, and measurement precision., Method: FHS participants completed several cognitive assessments including screening instruments and more comprehensive batteries at different study visits. We used expert opinion to assign each cognitive test item to a single domain-memory, executive function, language, visuospatial abilities, or none of the above. As part of a larger cross-study harmonization effort, we calibrated each domain separately using bifactor confirmatory factor analysis (CFA) models, incorporating item parameters for anchor items previously calibrated from other studies and freely estimating item parameters for FHS-specific items. We obtained scores and standard errors (SEs) for each participant at each study visit. We addressed psychometric considerations of ceiling effects and measurement precision., Results: Overall, memory domain scores were the most precisely estimated. Scores for all domains from visits where the Mini-Mental State Examination (MMSE) was the only test administered were imprecisely estimated and suffered from ceiling effects. Scores from visits with a more extensive battery were estimated more precisely and better differentiated between ability levels., Conclusions: The harmonized and calibrated cognitive data from the FHS should prove useful for future analyses examining cognition and cognitive decline. They will be of particular interest when combining FHS with other studies that have been similarly calibrated. Researchers should be aware of varying levels of measurement precision and the possibility of ceiling effects in their planned analyses of data from the FHS and similar studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC., Method: We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts ( n = 2,712). We further demonstrated our method with the Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease (A4) Study prerandomized data ( n = 4,492). For the harmonization method, we used confirmatory factor analysis (CFA) on the final visit of the longitudinal cohorts to determine parameters to generate latent PACC (lPACC) scores. Overlapping tests across studies were set as "anchors" that tied cohorts together, while parameters from unique tests were freely estimated. We performed validation analyses to assess the performance of lPACC versus the common standardized PACC (zPACC)., Results: Baseline (BL) scores for the zPACC were centered on zero, by definition. The harmonized lPACC did not define a common mean of zero and demonstrated differences in baseline ability levels across the cohorts. Baseline lPACC slightly outperformed zPACC in the prediction of progression to dementia. Longitudinal change in the lPACC was more constrained and less variable relative to the zPACC. In combined-cohort analyses, longitudinal lPACC slightly outperformed longitudinal zPACC in its association with baseline β-amyloid status., Conclusions: This study proposes procedures for harmonizing the PACC that make fewer strong assumptions than the zPACC, facilitating robust multicohort analyses. This implementation of item response theory lends itself to adapting across future cohorts with similar composites. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction: Persons with military involvement may be more likely to have Parkinson's disease (PD) risk factors. As PD is rare, case finding remains a challenge, contributing to our limited understanding of PD risk factors. Here, we explore the validity of case-finding strategies and whether military employment is associated with PD., Materials and Methods: We identified Adult Changes in Thought (ACT) study participants reporting military employment as their longest or second longest occupation. We used self-report and prescription fills to identify PD cases and validated this case-finding approach against medical record review., Results: At enrollment, 6% of 5,125 eligible participants had military employment and 1.8% had prevalent PD; an additional 3.5% developed PD over follow-up (mean: 8.3 years). Sensitivity of our case-finding approach was higher for incident (80%) than prevalent cases (54%). Specificity was high (>97%) for both. Military employment was not associated with prevalent PD. Among nonsmokers, point estimates suggested an increased risk of incident PD with military employment, but the result was non-significant and based on a small number of cases., Conclusions: Self-report and prescription medications can accurately identify incident PD cases relative to the reference method of medical record review. We found no association between military employment and PD.

The 24-h activity cycle (24HAC) is a new paradigm for studying activity behaviors in relation to health outcomes. This approach inherently captures the interrelatedness of the daily time spent in physical activity (PA), sedentary behavior (SB), and sleep. We describe three popular approaches for modeling outcome associations with the 24HAC exposure. We apply these approaches to assess an association with a cognitive outcome in a cohort of older adults, discuss statistical challenges, and provide guidance on interpretation and selecting an appropriate approach. We compare the use of the isotemporal substitution model (ISM), compositional data analysis (CoDA), and latent profile analysis (LPA) to analyze 24HAC. We illustrate each method by exploring cross-sectional associations with cognition in 1,034 older adults (Mean age = 77; Age range = 65-100; 55.8% female; 90% White) who were part of the Adult Changes in Thought (ACT) Activity Monitoring (ACT-AM) sub-study. PA and SB were assessed with thigh-worn activPAL accelerometers for 7-days. For each method, we fit a multivariable regression model to examine the cross-sectional association between the 24HAC and Cognitive Abilities Screening Instrument item response theory (CASI-IRT) score, adjusting for baseline characteristics. We highlight differences in assumptions and the scientific questions addressable by each approach. ISM is easiest to apply and interpret; however, the typical ISM assumes a linear association. CoDA uses an isometric log-ratio transformation to directly model the compositional exposure but can be more challenging to apply and interpret. LPA can serve as an exploratory analysis tool to classify individuals into groups with similar time-use patterns. Inference on associations of latent profiles with health outcomes need to account for the uncertainty of the LPA classifications, which is often ignored. Analyses using the three methods did not suggest that less time spent on SB and more in PA was associated with better cognitive function. The three standard analytical approaches for 24HAC each have advantages and limitations, and selection of the most appropriate method should be guided by the scientific questions of interest and applicability of each model's assumptions. Further research is needed into the health implications of the distinct 24HAC patterns identified in this cohort., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Rosenberg, Greenwood-Hickman, McCurry, Proust-Lima, Nelson, Crane, LaCroix, Larson and Shaw.)

Individuals at distinct stages of Alzheimer's disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes at the synaptic level are observed in brain areas affected early in AD, and if they are emergent in MCI, is not clearly known. Equally important, it is not known whether global synaptic E/I imbalances correlate with the severity of cognitive impairment in the continuum of AD. Measuring the amplitude of ion currents of human excitatory and inhibitory synaptic receptors microtransplanted from the hippocampus and temporal cortex of cognitively normal, mildly cognitively impaired and AD individuals into surrogate cells, we found regional differences in pro-excitatory shifts of the excitatory to inhibitory (E/I) current ratio that correlates positively with toxic proteins and degree of pathology, and impinges negatively on cognitive performance scores. Using these data with electrophysiologically anchored analysis of the synapto-proteome in the same individuals, we identified a group of proteins sustaining synaptic function and those related to synaptic toxicity. We also found an uncoupling between the function and expression of proteins for GABAergic signaling in the temporal cortex underlying larger E/I and worse cognitive performance. Further analysis of transcriptomic and in situ hybridization datasets from an independent cohort across the continuum of AD confirm regional differences in pro-excitatory shifts of the E/I balance that correlate negatively with the most recent calibrated composite scores for memory, executive function, language and visuospatial abilities, as well as overall cognitive performance. These findings indicate that early shifts of E/I balance may contribute to loss of cognitive capabilities in the continuum of AD clinical syndrome., (© 2022. The Author(s).)

Abstract: Modifications to Fried's frailty phenotype (FFP) are common. We evaluated a self-reported modified frailty phenotype (Mod-FP) used among people with HIV (PWH). Among 522 PWH engaged in two longitudinal studies, we assessed validity of the four-item Mod-FP compared with the five-item FFP. We compared the phenotypes via receiver operator characteristic curves, agreement in classifying frailty, and criterion validity via association with having experienced falls. Mod-FP classified 8% of PWH as frail, whereas FFP classified 9%. The area under the receiver operator characteristic curve for Mod-FP classifying frailty was 0.93 (95% CI = 0.91-0.96). We observed kappa ranging from 0.64 (unweighted) to 0.75 (weighted) for categorizing frailty status. Both definitions found frailty associated with a greater odds of experiencing a fall; FFP estimated a slightly greater magnitude (i.e., OR) for the association than Mod-FP. The Mod-FP has good performance in measuring frailty among PWH and is reasonable to use when the gold standards of observed assessments (i.e., weakness and slowness) are not feasible., (Copyright © 2023 Association of Nurses in AIDS Care.)

Background: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population., Methods: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies., Findings: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42])., Interpretation: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted., Funding: Gates Ventures., Competing Interests: Declaration of interests SS reports consulting fees from Biogen and Eisai. JS reports consulting fees from AVID, Alnylam Pharmaceuticals, and Cerveau Technologies. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Telephone-administered cognitive assessments are a cost-effective and sometimes necessary alternative to face-to-face assessments. There is limited information in large studies concerning mode effects, or differences in cognition attributable to the assessment method, as a potential measurement threat. We evaluated mode effects on cognitive scores using a population-based sample of community-living older adults., Methods: We used data from participants aged 65-79 in the 2014 Health and Retirement Study for whom the interview mode was randomized (n = 6,825). We assessed mode differences in test means, whether mode modifies associations of cognition with criterion variables, and formal measurement invariance testing., Results: Relative to face-to-face assessment, telephone assessment was associated with higher scores for memory and calculation (0.06 to 0.013 standard deviations [SD]) and lower scores for nonmemory items (-0.09 to -0.01 SD). Cognition was significantly differentially related to instrumental activities of daily living difficulty depending on assessment mode. Measurement invariance testing identified evidence of mode differences in certain tests as a function of mode: adjusting for underlying cognition, the largest mode differences in memory and attention: immediate noun recall, delayed word recall, and serial-7s scores were higher given telephone administration., Discussion: Differences by mode of administration are apparent in cognitive measurement in older adults, albeit to a small degree in our study, and most pronounced for tests of memory and attention. The importance of accounting for mode differences ultimately depends on one's research question and study sample: not all associations may be affected by mode differences, and such modification may only be apparent among those with lower cognitive functioning., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The aim of this study was to analyze a publicly available sample of rule-based phenotype definitions to characterize and evaluate the variability of logical constructs used., Materials and Methods: A sample of 33 preexisting phenotype definitions used in research that are represented using Fast Healthcare Interoperability Resources and Clinical Quality Language (CQL) was analyzed using automated analysis of the computable representation of the CQL libraries., Results: Most of the phenotype definitions include narrative descriptions and flowcharts, while few provide pseudocode or executable artifacts. Most use 4 or fewer medical terminologies. The number of codes used ranges from 5 to 6865, and value sets from 1 to 19. We found that the most common expressions used were literal, data, and logical expressions. Aggregate and arithmetic expressions are the least common. Expression depth ranges from 4 to 27., Discussion: Despite the range of conditions, we found that all of the phenotype definitions consisted of logical criteria, representing both clinical and operational logic, and tabular data, consisting of codes from standard terminologies and keywords for natural language processing. The total number and variety of expressions are low, which may be to simplify implementation, or authors may limit complexity due to data availability constraints., Conclusions: The phenotype definitions analyzed show significant variation in specific logical, arithmetic, and other operators but are all composed of the same high-level components, namely tabular data and logical expressions. A standard representation for phenotype definitions should support these formats and be modular to support localization and shared logic., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)