👤 D Yaffe

To determine whether genetic ancestry modulates Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ In the full cohort, Genetic ancestry modifies the effect of Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less

We aimed to examine how coronary artery calcium (CAC) and its progression relate to cognitive function in midlife, an important time for cognitive aging. We studied participants enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study, a longitudinal cohort of Black and White adults aged 18 to 30 years at baseline, who completed CAC measurements using computed tomography at year 15 (2000-2001; our baseline), had at least 1 follow-up CAC measurement at years 20 (2005-2006) or 25 (2010-2011), and completed cognitive assessments with a battery of 5 tests at years 30 (2015-2016) or 35 (2020-2022). CAC progression was defined as: (1) CAC >0 at follow-up among participants with baseline CAC=0; (2) an annualized change of ≥10 units at follow-up among those with 00) and CAC progression. Among the 2341 participants (mean baseline age 40.3±3.6 years; 56% female), baseline CAC >0 (9%) was associated with lower processing speed, verbal memory, and global cognition, whereas CAC progression (26%) was associated with lower processing speed and global cognition after adjusting for demographics, education, physical activity, depressive symptoms, APOE ε4 allele, and baseline CAC score. The standardized cognitive differences (95% CI) for CAC progression versus no progression were -0.14 (95% CI, -0.23 to -0.06) for the Digit Symbol Substitution Test and -0.09 (95% CI, -0.17 to -0.01) for the Montreal Cognitive Assessment. CAC progression was associated with worse midlife processing speed and global cognition, independent of baseline CAC score and established risk factors. Repeated CAC assessments may offer clinical value for identifying individuals at increased risk for midlife cognitive decline. Show less

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 Show less