Epigenomic features related to microglia are associated with attenuated effect of APOE epsilon 4 on Alzheimer's disease risk in humans

Not all apolipoprotein E (APOE) epsilon 4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of epsilon 4 on AD may exist. Guided by the top epsilon 4-attenuating signals from methylome-wide association analyses (N = 572, epsilon 4+ and epsilon 4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the epsilon 4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principal component (PC1), which interacts with epsilon 4 on AD, and is associated with expression of innate immune genes and activated microglia. In epsilon 4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (odds ratio = 2.39, 95% confidence interval = [1.64,3.46], P = 7.08 x 10(-6)). An epigenomic factor associated with a reduced proportion of activated microglia (epigenomic factor of activated microglia, EFAM) appears to attenuate the risk of epsilon 4 on AD.