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Abstract 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

Abstract 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.

Abstract Background Research supports that moderate-to-vigorous intensity physical activity (MVPA) is key to prolonged health and function. Among older adults, substantial changes to MVPA may be infeasible, thus a growing literature suggests a shift in focus to whole-day activity patterns. Methods With data from 795 older adults aged 65–100 in the Adult Changes in Thought Activity Monitoring study, we used linear regression to estimate associations between ActiGraph and activPAL measured activity patterns – including light intensity physical activity, steps, standing, and sedentary behaviors – and physical function as measured by a short Performance-based Physical Function (sPPF) score (range 0–12), a composite score based on three standardized physical performance tasks: gait speed, timed chair stands, and grip strength. We examined whether relationships persisted when controlling for MVPA or differed across age, gender, or quartiles of MVPA. Results In models unadjusted for MVPA, a 1-standard deviation (SD) increment of daily sitting (1.9 h more), mean sitting bout duration (8 min longer average), or time spent in sedentary activity (1.6 h more) was associated with ~ 0.3–0.4 points lower mean sPPF score (all p

Abstract Background Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. Methods We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. Results We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. Conclusions Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

Abstract Background Few studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT). Methods The ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent. Results Among 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603–618 min/day), 3.9 h/day (226–239 min/day), and 1.4 h/day (79–84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude [VM] 518 counts/15 s) physical activity durations were 9.5 h/day (565–577 min/day), 4.5 h/day (267–276 min/day), and 1.0 h/day (59–64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity. Conclusions Our recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.

Abstract Alzheimer’s disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

Abstract Background Detecting patients with undiagnosed dementia is an important clinical challenge. Changes in medication adherence might represent an early sign of cognitive impairment. We sought to examine antihypertensive and statin adherence trajectories in community-dwelling older adults, comparing people who went on to develop dementia to those who did not. Methods We analyzed data from Adult Changes in Thought (ACT), a population-based cohort study embedded within an integrated healthcare delivery system. Analyses included 4368 participants aged ≥65 years who had at least one follow-up visit. Research-quality dementia diagnoses were used to identify cases. We selected non-dementia control visits matched on age, sex, and study cohort that occurred at similar ACT follow-up time as the case’s dementia onset; we treated this as the index date. Participants were included if they were prevalent users of either a statin or antihypertensive medication on the first day of follow up – 3 years prior to the index date. Using prescription fill dates and days supply, we calculated daily binary medication availability measures for each participant (‘days covered’) over 3 years leading up to the index date. We used group-based trajectory models to identify patterns of antihypertensive and statin adherence, and used conditional logistic regression to examine associations between adherence trajectories and dementia. Results Four trajectories were identified for antihypertensive users (292 cases, 3890 control visits), including near perfect (n = 1877, 36.6% cases, 45.5% controls), high (n = 1840, 43.2% cases, 44.1% controls), moderate (n = 365, 18.5% cases, 8.0% controls) and early poor adherence (n = 100, 1.7% cases, 2.4% controls). Odds of dementia was 3 times greater for those with moderate antihypertensive adherence compared to those with near perfect adherence (adjusted OR 3.0, 95% CI 2.0, 4.3). Four trajectories were identified for statin users (148 cases, 1131 control visits), including high (n = 1004, 75.0% cases, 79.0% controls), moderate (n = 192, 19.6% cases, 14.4% controls), early poor (n = 43, 2.0% cases, 3.5% controls), and delayed poor adherence (n = 40, 3.4% cases, 3.1% controls). No association was detected between statin adherence trajectories and dementia. Conclusions Patterns of medication adherence may be useful to identify a subset of people at higher likelihood of developing dementia.

Abstract Background Mechanisms linking cognitive and physical functioning in older adults are unclear. We sought to determine whether brain pathological changes relate to the level or rate of physical performance decline. Methods This study analyzed data from 305 participants in the autopsy subcohort of the prospective Adult Changes in Thought (ACT) study. Participants were aged 65+ and free of dementia at enrollment. Physical performance was measured at baseline and every two years using the Short Physical Performance Battery (SPPB). Data from 3174 ACT participants with ≥2 SPPB measurements were used to estimate two physical function measures: 1) rate of SPPB decline defined by intercept and slope; and 2) estimated SPPB 5 years prior to death. Neuropathology findings at autopsy included neurofibrillary tangles (Braak stage), neuritic plaques (CERAD level), presence of amyloid angiopathy, microinfarcts, cystic infarcts, and Lewy bodies. Associations (adjusted for sex, age, body mass index and education) between dichotomized neuropathologic outcomes and SPPB measures were estimated using modified Poisson regression with inverse probability weights (IPW) estimated via Generalized Estimating Equations (GEE). Relative risks for the 20th, 40th, and 60th percentiles (lowest levels and highest rates of decline) relative to the 80th percentile (highest level and lowest rate of decline) were calculated. Results Decedents with the least vs. most SPPB decline (slope > 75th vs.

An amendment to this paper has been published and can be accessed via the original article.