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Background  The  apolipoprotein E  ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of  APOE  between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.    Methods  Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free  APOE  ε4 ( n  = 2469) and ε2 ( n  = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.    Results  We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of  APOE  and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of  APOE : differentially methylated positions were identified in  DHCR24 ,  LDLR  and  ABCG1  (2.59 × 10 −100  ≤  P  ≤ 2.44 × 10 −8 ) and DMRs were identified in  SREBF2  and  LDLR  (1.63 × 10 −4  ≤  P  ≤ 3.01 × 10 −2 ). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in  ABCG1  and  DHCR24 .    Conclusions   APOE  ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in  trans  as well as  cis  to  APOE  and implicate genes involved in lipid homeostasis.

Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles