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

Abstract

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 PRS×APOE 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×APOE ε4×age 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.

Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals

“…Past epidemiological studies have investigated how lifestyle choices affect the genetic risk of LOAD, yielding mixed results 15,16,39,40 , with some null findings even in a large sample 15 . Recent research has demonstrated that age modifies LOAD genetic risk 18,41,42 and that PRS effects on LOAD-related traits are stronger among APOE-ε4 carriers 22,[43][44][45] . However, these findings have not been integrated into previous genelifestyle interaction analyses, as the present analysis does.…”

“…First, adhering to a healthy lifestyle might influence when genetic effects become noticeable throughout one’s life. Prior work suggested adverse PRS effects emerged by age 70 in APOE-ε4 carriers 22 . The present analysis in the same cohort suggests that among APOE-ε4 carriers with the least healthy habits, cognitive decline begins approximately 1-3 years earlier, although this was not replicated in HRS.…”

“…Details about genotyping and quality control have been described elsewhere 21 . The non- APOE PRS is a weighted sum (∼N(0,1)) of independent single-nucleotide polymorphisms that have shown genome-wide significant ( P <5e −8 , excluding APOE ) association with AD 2,22 . A higher PRS corresponds to a higher genetic risk of LOAD.…”