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Cited by 49Epigenetics and DNA MethylationAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism

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Klein, Hans-Ulrich, Bennett, David A., De Jager, Philip L.·2016·Acta Neuropathologica
DOI 10.1007/s00401-016-1612-7PMC PMC5189639
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Abstract

The advent of new technologies and analytic approaches is beginning to provide an unprecedented look at features of the human genome that affect RNA expression. These "epigenomic" features are found in a number of different forms: they include DNA methylation, covalent modifications of histone proteins and non-coding RNAs. Some of these features have now been implicated in Alzheimer's disease (AD). Here, we focus on recent studies that have identified robust observations relating to DNA methylation and chromatin in human brain tissue; these findings will ground the next generation of studies and provide a model for the design of such studies. Stemming from observations that compounds with histone deacetylase activity may be beneficial in AD, epigenome-wide studies in cortical samples from large numbers of human subjects have now shown that AD-associated epigenomic changes are reproducible, are not driven by genetic risk factors, and are widespread at specific locations in the genome. A fundamental question of whether such changes are causal remains to be demonstrated, but it is already clear that well-powered investigations of the human epigenome in the target organ of a neurodegenerative disease are feasible, are implicating new areas of the genome in the disease, and will be an important tool for future studies. We are now at an inflection point: as genome-wide association studies of genetic variants come to an end, a new generation of studies exploring the epigenome will provide an important new layer of information with which to enrich our understanding of AD pathogenesis and to possibly guide development of new therapeutic targets.

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  • The limited commonality between genetic and epigenetic loci in AD could be due to low power in EWAS and/or GWAS but could also reflect relatively independent roles of genetic variants and DNA methylation in influencing AD susceptibility.

    “The limited commonality between genetic and epigenetic loci in AD could be due to the low power in EWAS and/or GWAS but could also reflect the relatively independent roles of genetic variants and DNA methylation in influencing AD susceptibility [65, 66].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [65]

    In “First generation of epigenomic studies in AD” (page unavailable), the review says validated AD epigenomic associations do not appear to be driven by genetic variation and describes genetic and methylation associations at BIN1 as independently influencing risk. It discusses sample size and statistical power, but does not identify low power in EWAS or GWAS as an explanation for limited overlap between loci. (LLM, conf=0.84)

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Sorted by citations

Authors
Klein, H.-U., Bennett, D. A., & De Jager, P. L.
Affiliations
  • Broad Institute (US)
  • Rush University Medical Center (US)
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2016-08-29
Volume
132
Issue
4
Pages
503-514
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-016-1612-7
PMC
PMC5189639
OpenAlex
W2507676175
Cited by
49
References
13
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 2
FWCI
0.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01 AG036042, R01 AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574)
  • National Institute of Environmental Health Sciences (U01 ES017155)
  • National Center for Research Resources (KL2 RR024151)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, epigenome, DNA methylation, histone modifications, chromatin, histone deacetylase inhibitors, non-coding RNA, human brain tissue, cortical tissue, epigenome-wide association study, gene discovery, pathogenesis, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Protein Processing, Post-Translational, Genetic Predisposition to Disease, Epigenesis, Genetic, Genome-Wide Association Study

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