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

INTRODUCTIONVariation in preclinical cognitive decline suggests additional genetic factors related to Alzheimers disease (e.g., a non-APOE polygenic risk scores [PRS]) may interact with the APOE {varepsilon}4 allele to influence cognitive decline. METHODSWe tested the PRS{xi}APOE {varepsilon}4{xi}age interaction on preclinical cognition using longitudinal data from the Wisconsin Registry for Alzheimers Prevention. All analyses were fitted using a linear mixed-effects model and adjusted for within individual/family correlation among 1,190 individuals. RESULTSWe found statistically significant PRS{xi}APOE {varepsilon}4{xi}age interactions on immediate learning (P=0.038), delayed recall (P<0.001), and Preclinical Alzheimers Cognitive Composite 3 score (P=0.026). PRS-related differences in overall and memory-related cognitive domains between people with and without APOE {varepsilon}4 emerge around age 70, with a much stronger adverse PRS effect among APOE {varepsilon}4 carriers. The findings were replicated in a population-based cohort. DISCUSSIONAPOE {varepsilon}4 can modify the association between PRS and cognition decline. HighlightsO_LIAPOE {varepsilon}4 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 < 5e-8). C_LIO_LIThe adverse genetic effect caused by the combined effect of the currently known genetic variants is more detrimental among APOE {varepsilon}4 carriers around age 70. C_LIO_LIIndividuals who are APOE {varepsilon}4 carriers with high PRS are the most vulnerable to the harmful effects caused by genetic burden. C_LI