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INTRODUCTION: The Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD), while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers but associations with epigenome-wide methylation are unknown. METHODS: The EPIC array was used to identify methylation differences between AD-free APOE ε4 (n=2469) and ε2 (n=1108) carriers using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and meQTL analyses. RESULTS: Differentially methylated positions were identified in APOE, surrounding genes and genes outside of this locus (DHCR24, LDLR and ABCG1). DMRs were identified in SREBF2, LDLR and SQLE. Pathway and meQTL analyses implicated lipid-related processes; however, blood cholesterol levels could not fully account for the associations. DISCUSSION: APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in cis and trans in genes involved in lipid homeostasis.

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