Dementia polygenic score links to dementia, disability, and death
Compared with favorable profiles, poor dementia polygenic profiles were associated with a 1.43 hazard ratio for a composite of dementia, disability, or death.
medRxiv
In a prospective study of 14,333 U.S. adults from the Health and Retirement Study (median age 55 years), researchers evaluated whether an integrated polygenic risk score for dementia was associated with dementia- and disability-free survival. The score combines neurodegenerative and vascular genetic components to classify individuals into favorable, intermediate, or poor profiles. Compared with a favorable profile, intermediate profiles were associated with an adjusted hazard ratio of 1.14 and poor profiles with a hazard ratio of 1.43 for the composite outcome of dementia, disability, or death. The association was strongest for dementia alone, where poor profiles showed a hazard ratio of 1.58 compared to favorable profiles, alongside hazard ratios of 1.43 for disability and 1.33 for death. Having both a poor polygenic profile and an APOE ε4 allele was associated with a 2.32 hazard ratio for dementia compared to non-carriers with favorable profiles.
Why it matters
The findings suggest that multi-trait genetic scores combining vascular and neurodegenerative risks may help stratify individuals for broader healthspan outcomes, including dementia- and disability-free survival. This approach could aid risk assessment in trials evaluating interventions targeting cognitive and functional decline.
Caveats
The observational design cannot establish causality, and the work is a preprint that has not yet completed peer review. The authors also highlight limitations related to genetic ancestry representation, broad generalizability, and clinical translation.
The paper
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Shufan Huo, Andrew Silberfeld, Tim D’Aoust, Stéphanie Debette, Adam de Havenon, Thomas M. Gill,Yale University
medRxiv · 11 Sep 2026 · Preprint, not peer-reviewed