Apolipoprotein E moderates the association between Non-APOEPolygenic 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- APOE polygenic risk scores [PRS]) may interact with the APOE ε4 allele to influence cognitive decline. METHODS We tested the PRSξ APOE ε4ξage 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 PRSξ APOE ε4ξage interactions on immediate learning ( P =0.038), delayed recall ( P <0.001), and Preclinical Alzheimer’s Cognitive Composite 3 score ( P =0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE ε4 emerge around age 70, with a much stronger adverse PRS effect among APOE ε4 carriers. The findings were replicated in a population-based cohort. DISCUSSION APOE ε4 can modify the association between PRS and cognition decline. Highlights APOE ε4 can modify the association between PRS and longitudinal cognition decline, with the modifying effects more pronounced when the PRS is constructed using a conservative P -threshold (e.g., P < 5 e-8 ). The adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental among APOE ε4 carriers around age 70. Individuals who are APOE ε4 carriers with high PRS are the most vulnerable to the harmful effects caused by genetic burden.