Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans.
Alzheimers Dement
; 18(4): 688-699, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-34482628
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apolipoproteína E4
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Doença de Alzheimer
Tipo de estudo:
Etiology_studies
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Risk_factors_studies
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Systematic_reviews
Limite:
Humans
Idioma:
En
Revista:
Alzheimers Dement
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos