Multi-trait Polygenic Profiling and Dementia- and Disability-free Survival: Results from the Health and Retirement Study (P5-13.001)

Objective
To determine whether multi-trait polygenic profiling influences dementia- and disability-free survival in older adults.
Background
Clinical trials of brain health and aging increasingly use holistic patient-centered outcomes that capture overall health status. PREVENTABLE, the first aging-focused statin trial in healthy older adults, evaluates dementia- and disability-free survival as its primary outcome. We hypothesized that adverse polygenic profiles of dementia are associated with higher risk of dementia, disability or death.
Design/Methods
We analyzed data from the Health and Retirement Study, a longitudinal cohort of older adults (1992–2020). Multi-trait polygenic profiling, represented by a polygenic risk score of neurodegenerative and vascular components of dementia, was estimated using a validated approach and categorized into favorable (< 20%), intermediate (20–80%) and poor (> 80%). We evaluated a composite outcome of time to dementia, disability, or death. The primary analysis included all participants without prior dementia or disability. The secondary analysis was restricted to the PREVENTABLE-eligible population, focusing on participants aged ≥75 without prior dementia, disability or cardiovascular disease.
Results
In the primary analysis (n=14,743; median follow-up: 18 years (interquartile range [IQR] 12–24), 6,804 participants (46%) developed the composite outcome. Compared to favorable polygenic profile, intermediate (HR 1.17, 95% CI 1.09–1.26) and poor (HR 1.59, 95% CI 1.36–1.87) profiles were significantly associated with higher hazard of the composite outcome. In the secondary analysis (n=3,195; median follow-up: 7 years (IQR 4–11)), 1,326 participants (42%) developed the composite outcome. Intermediate (HR 1.22, 95% CI 1.05–1.43) and poor (HR 1.48, 95% CI 1.19–1.84) profiles remained significantly associated with higher hazard.
Conclusions
Intermediate and poor polygenic profiles are significantly associated with higher risk of dementia, disability, or death. People with adverse profiles may derive additional therapeutic benefit from statins in PREVENTABLE. Incorporating genetic stratification into clinical trials may improve interpretation of treatment effects and help identify patients most likely to benefit from interventions.