Greater Effect of Polygenic Risk Score for Alzheimer's Disease Among Younger Cases Who are Apolipoprotein E-ϵ4 Carriers

Abstract

Polygenic risk scores (PRS) have the potential to serve as a low-cost, non-invasive screening method for Alzheimers disease (AD). However, to what extent age and the Apolipoprotein E-{varepsilon}4 (APOE4) risk allele influence the effect of PRS is underexplored. In a cohort of 346 superager controls (age [≥] 90 years), 2,930 controls (age 60-89) and 1,760 AD cases, we computed APOE-independent PRS for AD. When using superager controls, subjects with PRS in the top decile had nearly five times greater odds of having AD than subjects in the lowest decile (OR=4.91, P=2.24x10-6). In our cross-sectional cohort, PRS modifies the age of onset for AD among APOE4 carriers, but not among non-carriers. Among APOE4 carriers, PRS in the top decile was associated with a five years earlier AD onset than the lowest decile (70.0 vs 75.0 years; t-test P=2.4x10-5). These findings suggest that APOE-independent genetic risk disproportionally affects younger APOE4 carriers, leading to earlier disease onset, while older controls carry less genetic risk.