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 (Aβ)/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 ε4 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 Aβ/tau pathology (plasma pTau 181 , plasma pTau 217 /Aβ 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 ε4 was strongly associated with worse Aβ/tau latent variable (β=0.31; p<0.001), with smaller but significant associations with neurodegeneration (β=0.085; p<0.001) and cognition (β=0.083; p<0.001). Higher AD-PRS was modestly associated with worse Aβ/tau (β=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration (β=0.16; p<0.001) but not with Aβ/tau or cognition. Adverse SDoH was associated with worse neurodegeneration (β=0.071; p<0.05) and strongly associated with worse cognition (β=0.22; p<0.001), with no associations with Aβ/tau. Conclusion and Relevance Genetic risks were primarily associated with Aβ 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. Key Points Questions Do Alzheimer’s disease (AD) risk factors differentially influence underlying AD pathophysiological processes, and do these associations vary across demographic subgroups? Findings Genetic and genomic risk burdens demonstrated the strongest associations with amyloid and tau pathology; clinical risk burden with neurodegeneration; and adverse social determinants of health with cognition. Meaning Because of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient. AD risk assessment should leverage multidomain frameworks incorporating genomic, clinical, and social determinants of health information to better inform disease development and progression.