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

Yiyi Ma, Lei Yu, Marta Olah, Rebecca Smith, Stephanie R. Oatman, Mariet Allen, Ehsan Pishva, Bin Zhang, Vilas Menon, Nilüfer Ertekin-Taner, Katie Lunnon, David A. Bennett, Hans Ulrich Klein, Philip L. De Jager

Research output: Contribution to journalArticlepeer-review

Abstract

Not all apolipoprotein E (APOE) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. 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. Three out of the four significant CpG dinucleotides were captured by one principal 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% (odds ratio = 2.39, 95% confidence interval = [1.64,3.46], P = 7.08 × 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 ε4 on AD.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2021

Keywords

  • Alzheimer's disease
  • apolipoprotein E
  • epigenome
  • microglia

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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