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Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer’s disease risk in humans
Author(s) -
Ma Yiyi,
Yu Lei,
Olah Marta,
Smith Rebecca G.,
Pishva Ehsan,
Me Vilas,
Lun Katie,
Bennett David A.,
Klein HansUlrich,
De Jager Philip L.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043533
Subject(s) - microglia , epigenomics , neurodegeneration , neuroscience , pathological , disease , apolipoprotein e , odds ratio , innate immune system , neuroinflammation , senile plaques , alzheimer's disease , biology , medicine , immunology , immune system , pathology , inflammation , dna methylation , gene expression , gene , genetics
Background Not all APOE ε4 carriers who survive to advanced age develop Alzheimer’s disease (AD); factors attenuating the ε4 risk on AD may exist. Method 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. Result Three out of the four significant CpG sites were captured by one principle component (PC1), which interacts with ε4 on AD, and is associated with expressions of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 59% (OR = 2.41, 95%CI = [1.64,3.52], P = 7.40 × 10 −6 ). Conclusion An epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of ε4 on AD.