ASSOCIATION OF CHOLESTEROL AND CHOLESTEROL METABOLISM GENES WITH COGNITIVE FUNCTION IN A POPULATION ENRICHED FOR A PARENTAL HISTORY OF ALZHEIMER’S DISEASE

Abstract

APOE ε4 and ABCA7 variants are susceptibility genes for Alzheimer's disease (AD). Both genes are involved in the cholesterol metabolism pathway, and mid-life cholesterol levels are associated with increased risk for AD. The interaction between APOE ε4 and ABCA7has been associated with three cognitive factor scores, Verbal Learning & Memory, Working Memory, and Immediate Memory, in a study of participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal study of middle-aged adults enriched for a parental history of AD. As a follow-up to this study, we sought to examine the influence of total serum cholesterol on this interaction effect. Linear mixed models were used to test the influence of total serum cholesterol on the APOE ε4 x ABCA7effect on the three cognitive factor scores (n=778). Each model was adjusted for age, gender, and the top two principal components of ancestry while including random effects for family (siblings) and participant (repeated measures). Continuous serum cholesterol measures were included as a covariate where appropriate. The addition of serum cholesterol to the model did not attenuate the previously reported effect of the APOE ε4 x ABCA7 interaction on the three cognitive factor scores, suggesting serum cholesterol is not in the causal pathway for this association. When stratifying the population by mean total serum cholesterol, the effect of the APOE ε4 x ABCA7 interaction on all three cognitive factor scores differed by tertile and ABCA7SNP. Total serum cholesterol was not found to be in the causal pathway of the APOE ε4 x ABCA7 interaction, but did appear to be a modifier of the interaction effect on the cognitive factor scores. APOE ε4 and ABCA7 genotypes along with cholesterol levels should be considered together when addressing cognitive function in at-risk populations.