Few studies have examined impairment in multiple senses (multisensory impairment) and risk of dementia in comparison to having a single or no sensory impairment. We studied 1,810 black and white non-demented participants from Health, Aging, and Body Composition (Health ABC) Study aged 70–79 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 ≥1.5 Standard Deviation decline in Modified Mini-Mental State Exam 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. Sensory impairments were common: 28% had visual impairment, 35% had hearing loss, 22% had poor smell, 12% had touch insensitivity; 26% had 2+ impairments, and 5.6% had 3+ sensory impairments. Number of impairments was associated with risk of dementia in a graded fashion (p<0.001). Compared to no sensory impairments, the adjusted Hazard Ratio (HR) was 1.5 (95%CI:1.1,2.0) for 1 sensory impairment, 1.9 (95%CI:1.4,2.6) for 2 sensory impairments, and 2.8 (95%CI:1.9,4.3) for 3+ sensory impairments. 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.

Preliminary evidence suggests that neighborhood environments, such as socioeconomic disadvantage, pedestrian and physical activity infrastructure, and availability of neighborhood destinations (e.g., parks), may be associated with late-life cognitive functioning and risk of Alzheimer’s disease and related disorders (ADRD). The supposition is that these neighborhood characteristics are associated with factors such as mental health, environmental exposures, health behaviors, and social determinants of health that in turn promote or diminish cognitive reserve and resilience in later life. However, observed associations may be biased by self-selection or reverse causation, such as when individuals with better cognition move to denser neighborhoods because they prefer many destinations within walking distance of home, or when individuals with deteriorating health choose residences offering health services in neighborhoods in rural or suburban areas (e.g., assisted living). Research on neighborhood environments and ADRD has typically focused on late-life brain health outcomes, which makes it difficult to disentangle true associations from associations that result from reverse causality. In this paper, we review study designs and methods to help reduce bias due to reverse causality and self-selection, while drawing attention to the unique aspects of these approaches when conducting research on neighborhoods and brain aging.

Objective To test the hypothesis that incipient Alzheimer disease (AD) may adversely affect hearing and that hearing loss may adversely affect cognition, we evaluated whether genetic variants that increase AD risk also increase problem hearing and genetic variants that increase hearing impairment risk do not influence cognition. Methods UK Biobank participants without dementia ≥56 years of age with Caucasian genetic ancestry completed a Digit Triplets Test of speech-in-noise hearing (n = 80,074), self-reported problem hearing and hearing with background noise (n = 244,915), and completed brief cognitive assessments. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related polymorphisms. A genetic risk score for hearing (hearing-GRS) was calculated using 3 previously identified polymorphisms related to hearing impairment. Using age-, sex-, and genetic ancestry–adjusted logistic and linear regression models, we evaluated whether the AD-GRS predicted poor hearing and whether the hearing-GRS predicted worse cognition. Results Poor speech-in-noise hearing (>-5.5-dB speech reception threshold; prevalence 14%) was associated with lower cognitive scores (ß = −1.28; 95% confidence interval [CI] −1.54 to −1.03). Higher AD-GRS was significantly associated with poor speech-in-noise hearing (odds ratio [OR] 1.06; 95% CI 1.01–1.11) and self-reported problems hearing with background noise (OR 1.03; 95% CI 1.00–1.05). Hearing-GRS was not significantly associated with cognitive scores (ß = −0.05; 95% CI −0.17 to 0.07). Conclusions Genetic risk for AD also influences speech-in-noise hearing. We failed to find evidence that genetic risk for hearing impairment affects cognition. AD disease processes or a that shared etiology may cause speech-in-noise difficulty before dementia onset.

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.

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.

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.