Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology

Importance: Alzheimer's disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive. Objective: To quantify the effects of risk factors across amyloid (A{beta})/tau, neurodegeneration, and cognition. Design: Cross-sectional analysis using structural equation modeling (SEM). Setting: Health and Aging Brain Study-Health Disparities (HABS-HD), a community-based cohort study. Participants: A total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit. Exposures: APOE e4 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis. Main Outcomes and Measures: Latent variables representing A{beta}/tau pathology (plasma pTau181, plasma pTau217/A{beta}42, amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language. Results: The total analytic sample included 2,276 participants (mean age: 65.3 {+/-} 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx/Hispanic adults: 40.8%). APOE e4 was strongly associated with worse A{beta}/tau latent variable ({beta}=0.31; p<0.001), with smaller but significant associations with neurodegeneration ({beta}=0.085; p<0.001) and cognition ({beta}=0.083; p<0.001). Higher AD-PRS was modestly associated with worse A{beta}/tau ({beta}=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration ({beta}=0.16; p<0.001) but not with A{beta}/tau or cognition. Adverse SDoH was associated with worse neurodegeneration ({beta}=0.071; p<0.05) and strongly associated with worse cognition ({beta}=0.22; p<0.001), with no associations with A{beta}/tau. Conclusion and Relevance: Genetic risks were primarily associated with A{beta} and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.