Multi-trait Polygenic Profiling and Survival Free of Dementia and Disability: Results from the Health and Retirement Study

ABSTRACT Objective: To determine whether a multi-trait polygenic profile for dementia is associated with dementia- and disability-free survival in middle-aged and older adults. Background: Clinical trials of brain health and aging increasingly use holistic, patient-centered outcomes that capture overall health status. Survival free of dementia and disability is one such outcome. We hypothesized that adverse polygenic profiles for dementia would be associated with higher risk of dementia, disability, or death. Design/Methods: We conducted a genetic association study within the Health and Retirement Study, a prospective, nationally representative longitudinal cohort of U.S. adults. Polygenic profiling used the previously validated integrated polygenic risk score for dementia (iPRS-DEM), which incorporates neurodegenerative and vascular genetic components. Participants were categorized as having favorable ([≤]20th percentile), intermediate (20th-80th percentile), or poor (>80th percentile) polygenic profiles. The primary outcome was a composite of dementia, disability, or death. Cox proportional hazards models were adjusted for age, sex, genetic ancestry, and genetic principal components. Interaction between continuous iPRS-DEM and APOE {varepsilon}4 status was assessed for 31-year outcome risk. Results: Among 45,234 HRS participants, 15,620 provided DNA samples, 15,565 had genotype data after quality control and imputation, and 14,333 were free of dementia and disability at baseline (median age 55 years; 58% female). Compared with a favorable polygenic profile, intermediate and poor profiles were associated with higher risk of the composite outcome (HR 1.14, 95% CI 1.07-1.21 and HR 1.43, 95% CI 1.26-1.63, respectively). The relative association was strongest for dementia; for poor versus favorable profiles, HRs were 1.58 (95% CI 1.21-2.05) for dementia, 1.43 (95% CI 1.14-1.79) for disability, and 1.33 (95% CI 1.15-1.54) for death. An interaction between continuous iPRS-DEM and APOE {varepsilon}4 status was observed for 31-year dementia risk (P=0.016). Relative to favorable-profile APOE {varepsilon}4 non-carriers, dementia risk was highest among participants with a poor profile who were APOE {varepsilon}4 carriers (HR 2.32, 95% CI 1.73-3.12). Conclusions: Adverse polygenic profiles for dementia were associated with higher composite risk of dementia, disability, or death in a large population-based cohort, with the strongest association observed for dementia. Joint consideration of iPRS-DEM and APOE {varepsilon}4 further identified individuals at elevated dementia risk. These findings support the potential value of polygenic profiling for risk stratification while highlighting limitations related to ancestry, generalizability, and clinical translation.