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bioRxiv · 10.1101/2020.09.28.317156

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

Ma, Y.·Yu, L.·Olah, M.·Smith, R.·Oatman, S. R.·Allen, M.·Pishva, E.·Zhang, B.·Menon, V.·Ertekin-Taner, N.·Lunnon, K.·Bennett, D. A.·Klein, H.-U.·De Jager, P.
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Abstract

INTRODUCTIONNot all APOE {varepsilon}4 carriers who survive to advanced age develop Alzheimers disease (AD); factors attenuating the risk of {varepsilon}4 on AD may exist. METHODSGuided by the top {varepsilon}4-attenuating signals from methylome-wide association analyses (N=572, {varepsilon}4+ and {varepsilon}4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the {varepsilon}4+ 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 {varepsilon}4 on AD, and is associated with expression of innate immune genes and activated microglia. In {varepsilon}4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (OR=2.39, 95%CI=[1.64,3.46], P=7.08x10-6). DISCUSSIONAn epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of {varepsilon}4 on AD.

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Ma, Y., Yu, L., Olah, M., Smith, R., Oatman, S. R., Allen, M., Pishva, E., Zhang, B., Menon, V., Ertekin-Taner, N., Lunnon, K., Bennett, D. A., Klein, H.-U., De Jager, P.. 2020-09-29. Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans. https://doi.org/10.1101/2020.09.28.317156

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