Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on alzheimer’s disease risk in humans

INTRODUCTION Not all APOE ε4 carriers who survive to advanced age develop Alzheimer’s disease (AD); factors attenuating the risk of ε4 on AD may exist. METHODS Guided by the top ε4-attenuating signals from methylome-wide association analyses (N=572, ε4+ and ε4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the ε4+ subgroups (N=235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. RESULTS Three out of the four significant CpG dinucleotides were captured by one principle component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (OR=2.39, 95%CI=[1.64,3.46], P =7.08×10 −6 ). DISCUSSION An epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of ε4 on AD.