@article{0be027af403a44409b197cb82a6d411d,
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.}",
note = "Funding Information: ROSMAP: We are grateful to the participants in the Religious Order Study, the Memory and Aging Project. This work is supported by the US National Institutes of Health (U01AG61356, R01 AG043617, R01 AG042210, R01 AG036042, R01 AG036836, R01 AG032990, R01 AG18023, RC2 AG036547, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG04190601, R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101). Ma Y. is supported by the 2019-AARF-644521. MSBB: Brain banking and neuropathology assessments for the Mount Sinai cohort was supported by US National Institutes of Health grants AG02219, AG05138, U01 AG046170, RF1 AG057440 and MH064673, and the Department of Veterans Affairs VISN3 MIRECC. Replication work in Boston was supported by US National Institutes of Health grants: R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151 and K25 AG041906-01. LBB: Brain banking and neuropathology assessments for the MRC London Neurodegenerative Diseases Brain Bank, which was supported by the Medical Research Council (UK), and Brains for Dementia Research (Alzheimer Brain Bank, UK). MAYO: Study data17 were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nil{\"u}fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinsons Research. We gratefully acknowledged Dr. Hyejung Won for his guidance to interpret the HiC sequencing data from the human fetal brains. Funding Information: : We are grateful to the participants in the Religious Order Study, the Memory and Aging Project. This work is supported by the US National Institutes of Health (U01AG61356, R01 AG043617, R01 AG042210, R01 AG036042, R01 AG036836, R01 AG032990, R01 AG18023, RC2 AG036547, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG04190601, R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101). Ma Y. is supported by the 2019‐AARF‐644521. : Brain banking and neuropathology assessments for the Mount Sinai cohort was supported by US National Institutes of Health grants AG02219, AG05138, U01 AG046170, RF1 AG057440 and MH064673, and the Department of Veterans Affairs VISN3 MIRECC. Replication work in Boston was supported by US National Institutes of Health grants: R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151 and K25 AG041906‐01. Brain banking and neuropathology assessments for the MRC London Neurodegenerative Diseases Brain Bank, which was supported by the Medical Research Council (UK), and Brains for Dementia Research (Alzheimer Brain Bank, UK). : Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nil{\"u}fer Ertekin‐Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinsons Research. We gratefully acknowledged Dr. Hyejung Won for his guidance to interpret the HiC sequencing data from the human fetal brains. ROSMAP MSBB LBB: MAYO 17 Publisher Copyright: {\textcopyright} 2021 the Alzheimer's Association.",
year = "2022",
month = apr,
doi = "10.1002/alz.12425",
language = "English (US)",
volume = "18",
pages = "688--699",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "4",
}