Author:
Ma Yiyi,Yu Lei,Olah Marta,Smith Rebecca,Oatman Stephanie R.,Allen Mariet,Pishva Ehsan,Zhang Bin,Menon Vilas,Ertekin-Taner Nilüfer,Lunnon Katie,Bennett David A.,Klein Hans-Ulrich,De Jager Philip L.
Abstract
AbstractINTRODUCTIONNot all APOE ε4 carriers who survive to advanced age develop Alzheimer’s disease (AD); factors attenuating the risk of ε4 on AD may exist.METHODSGuided 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.RESULTSThree 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).DISCUSSIONAn epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of ε4 on AD.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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