Phenotype‐informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease

Introduction Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Methods Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. Discussion AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.