Apolipoprotein E moderates the association between Non- Polygenic Risk Score for Alzheimer's Disease and Aging on Preclinical Cognitive Function.

Introduction: Variation in preclinical cognitive decline suggests additional genetic factors related to Alzheimer's disease (e.g., a non- polygenic risk scores [PRS]) may interact with the ε4 allele to influence cognitive decline.

Methods: We tested the PRS× ε4×age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimer's Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals.

Results: We found statistically significant PRS× ε4×age interactions on immediate learning (=0.038), delayed recall (<0.001), and Preclinical Alzheimer's Cognitive Composite 3 score (=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without ε4 emerge around age 70, with a much stronger adverse PRS effect among ε4 carriers. The findings were replicated in a population-based cohort.

Discussion: ε4 can modify the association between PRS and cognition decline.