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We examined associations of an Alzheimer's disease (AD) Genetic Risk Score (AD‐GRS) and midlife cognitive and neuroimaging outcomes in 1,252 middle‐aged participants (311 with brain MRI). A higher AD‐GRS based on 25 previously identified loci (excluding apolipoprotein E [APOE]) was associated with worse Montreal Cognitive Assessment (−0.14 standard deviation [SD] [95% confidence interval {CI}: ‐0.26, −0.02]), older machine learning predicted brain age (2.35 years[95%CI: 0.01, 4.69]), and white matter hyperintensity volume (0.35 SD [95% CI: 0.00, 0.71]), but not with a composite cognitive outcome, total brain, or hippocampal volume. APOE ε4 allele was not associated with any outcomes. AD risk genes beyond APOE may contribute to subclinical differences in cognition and brain health in midlife. ANN NEUROL 2023;93:629–634 [ABSTRACT FROM AUTHOR]

Recent high-profile failures of Alzheimer disease treatments at the clinical trial stage have led to renewed efforts to identify and test novel interventions for Alzheimer disease and related dementias (ADRD). In this Perspective, we highlight the importance of including well-designed observational studies as part of these efforts. Observational research is an important cornerstone for gathering evidence on risk factors and causes of ADRD; this evidence can then be combined with data from preclinical studies and randomized controlled trials to inform the development of effective interventions. Observational study designs can be particularly beneficial for hypothesis generation, posing questions that are unethical or impractical for a trial setting, studying life-course associations, research in populations typically not included in trials, and public health surveillance. Here, we discuss each of these situations in the specific context of ADRD research. We also highlight novel approaches to enhance causal inference and provide a timely discussion on how observational epidemiological studies help provide a bridge between preclinical studies and successful interventions for ADRD. [ABSTRACT FROM AUTHOR]

Objectives Late-life depression is a comorbidity that may co-occur in older adults with hearing loss—each has prevalent and independent modifiable risk factors for dementia. Methods Using data from 1,820 Health, Aging and Body Composition study participants (74 ± 2.8 years, 38% Black race), we compared the hearing loss–dementia/cognitive decline relationship between those with normal hearing/mild hearing loss and those with moderate or greater hearing loss. Using linear mixed-effects and Cox proportional hazard models, we investigated if the associations between hearing loss and cognitive decline or dementia (Modified Mini-Mental State [3MS] Examination and Digit Symbol Substitution Test [DSST]) differed by the presence or absence of depressive symptoms. Depressive symptoms were defined as Center for Epidemiologic Study—Depression scale 10 ≥10 at one or more visits from Years 1–5. Algorithmic incident dementia was defined using medication use, hospitalizations, and cognitive test scores. Audiometric hearing loss was measured at Year 5 and categorized as normal/mild versus moderate or greater hearing loss. Results Having both hearing loss and depressive symptoms (vs. having neither) was associated with faster rates of decline in 3MS Examination (β = −0.30; 95% confidence interval [CI]: −0.78, −0.19) and DSST (β = −0.35; 95% CI: −0.67, −0.03) over 10 years of follow-up. Having both hearing loss and depressive symptoms (vs. neither) was associated with increased risk (hazard ratio [HR]: 2.91; 95% CI: 1.59, 5.33 vs. HR: 1.54; 95% CI: 1.10, 2.15 hearing loss only and HR: 2.35; 95% CI: 1.56, 3.53 depressive symptoms only) of incident dementia in multivariable-adjusted Cox proportional hazards models. Discussion Comorbid conditions among hearing-impaired older adults should be considered and may aid in dementia prevention and management strategies. [ABSTRACT FROM AUTHOR]

The relationship between body mass index (BMI) and health outcomes of older adults, including dementia, remains controversial. Many studies find inverse associations between BMI and dementia among older adults, while in other studies high BMI in midlife is associated with increased dementia risk. In this issue, Li et al. (Am J Epidemiol. 2021;190(12):2503–2510) examine BMI from mid- to late life and risk of dementia using the extensive follow-up of the Framingham Offspring Study. They found changing trends in the association between BMI and dementia from a positive association for midlife (ages 40–49) to an inverse trend in late life. Their work demonstrates the importance of studying dementia risk factors across the life course. Midlife obesity might be an important modifiable risk factor for dementia. However, because incipient dementia can lead to weight loss, reverse causation remains a key source of bias that could explain an inverse trend between BMI and dementia in older ages. The extent of other biases, including unmeasured confounding, inaccuracy of BMI as a measure for adiposity, or selective survival, are also unclear. Triangulating evidence on body composition and dementia risk could lead to better targets for dementia intervention, but future work will need to evaluate specific pathways. [ABSTRACT FROM AUTHOR]

Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006–2010, who were without dementia, aged 39–73, with European genetic ancestry. BMI was calculated with measured height/weight (weight (kg)/height (m)2). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (β = 0.00, 95% confidence interval (CI): −0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (β = −0.03, 95% CI: −0.06, −0.01) and 60- to 73-year-olds (β = −0.09, 95% CI:−0.12, −0.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.Objective: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.Methods: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.Results: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).Conclusion: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms. [ABSTRACT FROM AUTHOR]

We used differences in state school policies as natural experiments to evaluate the joint influence of educational quantity and quality on late-life physical and mental health. Using US Census microsample data, historical measures of state compulsory schooling and school quality (term length, student-teacher ratio, and attendance rates) were combined via regression modeling on a scale corresponding to years of education (policy-predicted years of education (PPYEd)). PPYEd values were linked to individual-level records for 8,920 black and 14,605 white participants aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke study (2003–2007). Linear and quantile regression models estimated the association between PPYEd and Physical Component Summary (PCS) and Mental Component Summary (MCS) from the Short Form Health Survey. We examined interactions by race and adjusted for sex, birth year, state of residence at age 6 years, and year of study enrollment. Higher PPYEd was associated with better median PCS (β = 1.28, 95% confidence interval (CI): 0.40, 1.49) and possibly better median MCS (β = 0.46, 95% CI: –0.01, 0.94). Effect estimates were higher among black (vs. white) persons (PCS × race interaction, β = 0.22, 95% CI: –0.62, 1.05, and MCS × race interaction, β = 0.18; 95% CI: –0.08, 0.44). When incorporating both school quality and duration, this quasiexperimental analysis found mixed evidence for a causal effect of education on health decades later. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined impairment in multiple senses (multisensory impairment) and risk of dementia in comparison to having a single or no sensory impairment.Methods: We studied 1,810 black and white nondemented participants from Health, Aging, and Body Composition (Health ABC) Study aged 70-79 years at enrollment. Sensory impairment was determined at our study baseline (Year 3-5 of Health ABC) using established cut points for vision (Bailey-Lovie visual acuity and Pelli-Robson contrast sensitivity test), hearing (audiometric testing), smell (12-item Cross-Cultural Smell Identification Test), and touch (peripheral nerve function tests). Incident dementia over 10 years of follow-up was based on hospitalization records, dementia medications, or at least 1.5 SD decline in Modified Mini-Mental State Examination score (race-specific). Cox proportional hazard models with adjustment for demographics, health behaviors, and health conditions evaluated the relationship between risk of dementia and increasing number of sensory impairments.Results: Sensory impairments were common: 28% had visual impairment, 35% had hearing loss, 22% had poor smell, 12% had touch insensitivity; 26% had more than two impairments, and 5.6% had more than three sensory impairments. Number of impairments was associated with risk of dementia in a graded fashion (p < .001). Compared to no sensory impairments, the adjusted hazard ratio was 1.49 (95% CI: 1.12, 1.98) for one sensory impairment, 1.91 (95% CI: 1.39, 2.63) for two sensory impairments, and 2.85 (95% CI: 1.88, 4.30) for more than three sensory impairments.Conclusions: Multisensory impairment was strongly associated with increased risk of dementia. Although, the nature of this relationship needs further investigation, sensory function assessment in multiple domains may help identify patients at high risk of dementia. [ABSTRACT FROM AUTHOR]

Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease–type neuropathology. [ABSTRACT FROM AUTHOR]

We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the Adult Changes in Thought population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in the National Alzheimer's Coordinating Center ( p < 0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies. [ABSTRACT FROM AUTHOR]

We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies, and cognition in a large multicenter autopsy sample. Data were obtained from the National Alzheimer's Coordinating Center on autopsied subjects ( N = 3976) who died between 2002 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with Alzheimer's disease neuropathologic changes but a minority of cases were discrepant. CAA was absent in 22% ( n = 520) of subjects with frequent neuritic plaques but present in 20.9% ( n = 91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, nonhemorrhagic brain infarcts were more common in those with CAA pathology than without ( p = 0.007). In subjects without the APOE ε4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in patients without Alzheimer's disease may indicate a distinct cerebrovascular condition. [ABSTRACT FROM AUTHOR]

Background: Although self-rated health (SRH) and performance-based physical function (PPF) are both strong predictors of mortality, little research has investigated the relationships between them. The objective of this study was to evaluate longitudinal, bi-directional associations between SRH and PPF. Methods: We evaluated longitudinal associations between SRH and PPF in 3,610 adults aged 65–89 followed for an average of 4.8 (standard deviation [SD]: 4.4) years between 1994 and July 2011 in the Adult Changes in Thought study, a population-based cohort in the Seattle area. SRH was assessed with a single-item question in the ACT study. Participants were asked at each evaluation to rate their health as “excellent”, “very good”, “good”, “fair”, or “poor” in response to the question “In general, how would you rate your health at this time”. PPF scores (ranging from 0–16, with higher indicating better performance) included walking speed, chair rises, grip strength, and balance. Results: At the baseline visit, participants averaged 74.5 (SD: 5.8) years of age and 2,115 (58.6%) were female. In multivariable linear mixed models, PPF declined with age, with more rapid decreases associated with very good, good, and fair (vs. excellent) baseline SRH. Adjusted annual change in PPF was −0.17 points (95% confidence interval [CI]: −0.19, −0.15) for individuals with excellent baseline SRH and −0.21 points (95% CI: −0.22, −0.19) for participants with fair SRH. In multivariable generalized linear mixed models, lower baseline PPF quartiles were associated with lower odds of excellent/very good/good SRH at age 75, however, differences between baseline PPF quartiles diminished with age. Conclusions: These results suggest that less than excellent SRH predicts decline in physical functioning, however, poor physical functioning may not predict change in SRH in a reciprocal fashion. SRH provides a simple assessment tool for identifying individuals at increased risk for decline in physical function. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively 'pure' HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively "pure" HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. [ABSTRACT FROM AUTHOR]

Background We examined the relationship between baseline olfactory performance and incident significant depressive symptoms and longitudinal depression trajectories in well-functioning older adults. Inflammation and cognitive status were examined as potential mediators. Methods Older adults (n = 2 125, 71–82 years, 51% female, 37% Black) completed an odor identification task at Year 3 (our study baseline) of the Health, Aging, and Body Composition study. Cognitive assessments, depressive symptoms, and inflammatory markers were ascertained across multiple visits over 8 years. Discrete-time complementary log-log models, group-based trajectory models, and multivariable-adjusted multinomial logistic regression were employed to assess the relationship between baseline olfaction and incident depression and longitudinal depression trajectories. Mediation analysis assessed the influence of cognitive status on these relationships. Results Individuals with lower olfaction had an increased risk of developing significant depressive symptoms at follow-up (hazard ratio = 1.04, 95% confidence interval [CI]: 1.00, 1.08). Of the 3 patterns of longitudinal depression scores identified (stable low, stable moderate, and stable high), poorer olfaction was associated with a 6% higher risk of membership in the stable moderate (relative risk ratio [RRR] = 1.06, 95% CI: 1.02, 1.10)/stable high (RRR = 1.06, 95% CI: 1.00, 1.12) groups, compared to the stable low group. Poor cognitive status, but not inflammation, partially mediated the relationship between olfactory performance and incident depression symptom severity. Conclusions Suboptimal olfaction could serve as a prognostic indicator of vulnerability for the development of late-life depression. These findings underscore the need for a greater understanding of olfaction in late-life depression and the demographic, cognitive, and biological factors that influence these relationships over time. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have provided equivocal evidence of antidepressant use on subsequent cognitive impairment; this could be due to inconsistent modeling approaches. Our goals are methodological and clinical. We evaluate the impact of statistical modeling approaches on the associations between antidepressant use and risk of Mild Cognitive Impairment (MCI) in older adults with depression. Methods: 716 participants were enrolled. Our primary analysis employed a time-dependent Cox proportional hazards model. We also implemented two fixed-covariate proportional hazards models—one based on having ever used antidepressants during follow-up, and the other restricted to baseline use only. Results: Treating antidepressant use as a time-varying covariate, we found no significant association with incident MCI (HR = 0.92, 95% CI: 0.70, 1.20). In contrast, when antidepressant use was treated as a fixed covariate, we observed a significant association between having ever used antidepressants and lower risk of MCI (HR = 0.40, 95% CI: 0.28, 0.56). However, in the baseline-use only model, the association was non-significant (HR = 0.84, 95% CI: 0.60, 1.17). Discussion: Our results were dependent upon statistical models and suggest that antidepressant use should be modeled as a time-varying covariate. Using a robust time-dependent analysis, antidepressant use was not significantly associated with incident MCI among cognitively normal persons with depression. [ABSTRACT FROM AUTHOR]

Objective: We explored the associations of dual sensory impairment (DSI) with long-term depressive and anxiety symptoms as well as low perceived social support (LPSS) as a modifier of these associations.Methods: Multinomial logistic regression models were used to examine the associations of DSI and single sensory impairment (hearing [pure-tone average > 25 dB] and vision [impaired visual acuity and/or contrast sensitivity]) with long-term depressive symptom (≥8 on the 10-item Center for Epidemiologic Studies-Depression Scale) and anxiety symptom (present on the Hopkins Symptom Checklist) latent classes from group-based trajectory models (rare/never; mild/moderate increasing; chronically high) among 2102 Health, Aging and Body Composition Study participants (mean age:74.0 ± 2.8 years; 51.9 % female) over 10 years. Models were adjusted by demographic characteristics and cardiovascular risk factors, and LPSS. An additional model evaluated the two-way interaction between DSI and LPSS.Results: DSI was associated with increased risk of being chronically depressed (Risk Ratio, RR = 1.99, 95 % Confidence Interval, CI: 1.25, 3.17), not mild/moderate increasingly depressed (RR = 1.25, 95 % CI: 0.91, 1.71). DSI had increased risk of being mild/moderate increasingly anxious (RR = 1.60, 95 % CI: 1.16, 2.19) and chronically anxious (RR = 1.86, 95 % CI: 1.05, 3.27) groups, as compared to no impairments. Hearing impairment was associated with being mild/moderate increasingly anxious (RR = 1.34, 95 % CI: 1.01, 1.79). No other associations were found for single sensory impairments. LPSS did not modify associations.Limitations: Sensory measures were time-fixed, and LPSS, depression and anxiety measures were self-reported.Conclusions: Future research is warranted to determine if DSI therapies may lessen long-term chronically high depressive and anxiety symptoms. [ABSTRACT FROM AUTHOR]

Background: There is a dearth of studies examining the associations of objectively measured dual sensory impairment (DSI) with incident mobility and activities of daily life (ADL) difficulty longitudinally. Methods: Cox proportional hazards models were used to examine the associations of DSI and single sensory impairment (hearing, vision) with incident mobility difficulty (many problems or inability to walk ¼ mile and/or climb 10 steps) and ADL difficulty up to six years of follow‐up among 2020 participants of the Health, Aging, and Body Composition Study, a cohort of older adults aged 70–79 years from Pittsburgh, PA and Memphis, TN. Vision impairment (VI) was defined as impaired visual acuity (20/50 or worse on Bailey‐Lovie distance test) and contrast sensitivity (<1.3 log units on Pelli‐Robson test), and hearing impairment (HI) was defined as pure‐tone average in better‐hearing ear >25 decibels. Models were adjusted by age, race, sex, education, diabetes, depressive symptoms, hypertension, gait speed from 20‐meter walk, global cognition score, prevalent cardiovascular disease, and body mass index. Results: There were 23% with DSI (n = 459). DSI was associated with increased risk of both incident report of mobility (hazard ratio [HR] = 2.25, 95% confidence interval [CI]: 1.47, 3.43), and ADL difficulty (HR = 2.26, 95% CI: 1.50, 3.40). Neither VI nor HI alone was associated with risk of either outcome. Conclusions: DSI is associated with increased risk of incident mobility and ADL difficulty. Rehabilitation and adaptive environmental changes for individuals living with DSI may be important to maximize mobility and daily function. [ABSTRACT FROM AUTHOR]

Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84–3.07]; longitudinal: OR, 1.66 [95% CI, 1.46–1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48–4.01]; longitudinal: OR, 2.09 [95% CI, 1.37–3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences. [ABSTRACT FROM AUTHOR]

Growing evidence has suggested an association between sleep duration and Alzheimer's disease (AD), but it is unclear if sleep duration is a manifestation of the AD disease process. We studied whether genetic liability for AD predicts sleep duration using a genetic risk score (GRS) for AD (AD‐GRS), in 406,536 UK Biobank participants with European ancestry and without dementia at enrollment. Higher AD‐GRS score was associated with shorter sleep (b = −0.014, 95% confidence interval [CI] = −0.022 to −0.006), especially in those aged 55+. Using AD‐GRS as an instrumental variable for AD diagnosis, incipient AD reduced sleep duration by 1.87 hours (95% CI = 0.96, 2.78). Short sleep duration might be an early marker of AD. ANN NEUROL 2021;89:177–181 [ABSTRACT FROM AUTHOR]

Social support during childhood lays the foundation for social relationships throughout the life course and has been shown to predict a wide range of mental and physical health outcomes. Social support measured in late life is prospectively associated with better cognitive aging, but few studies have evaluated social support received earlier in the life course. We quantified the effects of childhood social support, reported retrospectively, on later-life cognitive trajectories and investigated biopsychosocial mechanisms underlying these associations. Latent growth curve models estimated 10-year cognitive trajectories in 8,538 participants (baseline ages 45-93; Mage = 63) in the REasons for Geographic And Racial Differences in Stroke (REGARDS) project. Independent of sociodemographics, childhood socioeconomic status, and household size, greater retrospective childhood social support was associated with better initial episodic memory, but not verbal fluency or cognitive change, in later adulthood. Associations with initial memory level were mediated by sociodemographic and psychosocial variables; specifically, those who reported greater childhood social support reported higher educational attainment and had better physical and emotional health in adulthood, which were each associated with better memory. These results provide support for broad and enduring effects of childhood social support on mental, physical, and cognitive health decades later. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer’s disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing. [ABSTRACT FROM PUBLISHER]