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

doi:10.1002/alz.12425

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	688-699
Number of pages	12
Journal	Alzheimer's and Dementia
Volume	18
Issue number	4
DOIs	https://doi.org/10.1002/alz.12425
State	Published - Apr 2022

Keywords

Alzheimer's disease
apolipoprotein E
epigenome
microglia

ASJC Scopus subject areas

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

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10.1002/alz.12425

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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. L. (2022). Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans. Alzheimer's and Dementia, 18(4), 688-699. https://doi.org/10.1002/alz.12425

Ma, Y, Yu, L, Olah, M, Smith, R, Oatman, SR, Allen, M, Pishva, E, Zhang, B, Menon, V, Ertekin-Taner, N, Lunnon, K, Bennett, DA, Klein, HU & De Jager, PL 2022, 'Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans', Alzheimer's and Dementia, vol. 18, no. 4, pp. 688-699. https://doi.org/10.1002/alz.12425

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

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.",

keywords = "Alzheimer's disease, apolipoprotein E, epigenome, microglia",

author = "Yiyi Ma and Lei Yu and Marta Olah and Rebecca Smith and Oatman, {Stephanie R.} and Mariet Allen and Ehsan Pishva and Bin Zhang and Vilas Menon and Nil{\"u}fer Ertekin-Taner and Katie Lunnon and Bennett, {David A.} and Klein, {Hans Ulrich} and {De Jager}, {Philip L.}",

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T1 - Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans

AU - Ma, Yiyi

AU - Yu, Lei

AU - Olah, Marta

AU - Smith, Rebecca

AU - Oatman, Stephanie R.

AU - Allen, Mariet

AU - Pishva, Ehsan

AU - Zhang, Bin

AU - Menon, Vilas

AU - Ertekin-Taner, Nilüfer

AU - Lunnon, Katie

AU - Bennett, David A.

AU - Klein, Hans Ulrich

AU - De Jager, Philip L.

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N2 - 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.

AB - 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.

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

Abstract

Keywords

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