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Cited by 363Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchEpigenetics and DNA Methylation

Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease

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Nativio, Raffaella, Donahue, Greg, Berson, Amit, Lan, Yemin, Amlie-Wolf, Alexandre, Tuzer, Ferit, Toledo, Jon B., Gosai, Sager J. +7 more·2018·Nature Neuroscience
DOI 10.1038/s41593-018-0101-9PMC PMC6124498
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Abstract

Aging is the strongest risk factor for Alzheimer’s disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD. By comparing the genome-wide profile of H4K16ac in AD with younger and elder controls, the authors propose a mechanism for how age is a risk factor for AD: a histone modification, whose accumulation is associated with aging, is dysregulated in AD.

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  • Gene expression alteration of Pcdh-γC5 has been detected in the brain of Alzheimer's disease patients and animal models of Alzheimer's disease, as well as neural cells generated from human iPSCs that express APOE4.

    “The gene expression alteration of Pcdh-γC5 has also been detected in the brain of AD patients and animal models of AD, as well as neural cells generated from human iPSCs that express APOE4, a prevalent genetic AD risk factor (Nativio et al., 2018;Meyer et al., 2019).”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Nativio et al., 2018

    The Results section (‘H4K16ac is redistributed during normal aging and AD’; page unavailable) reports gene-expression analysis in human AD brain samples, but does not identify altered Pcdh-γC5 expression. Searches for Pcdh-γC5/PCDHGC5, animal models, and APOE4-expressing iPSC-derived neural cells found no passage in our copy establishing the specific claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Pcdh-γC5 has been implicated in Alzheimer's disease pathogenesis.

    “Pcdh-γC5 has been implicated in AD pathogenesis (Nativio et al., 2018;Tao et al., 2024), prompting us to examine its expression in 5×FAD mice”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Nativio et al., 2018

    The Results section on AD-related H4K16ac changes discusses affected pathways but does not implicate Pcdh-γC5. Searches of our copy for “Pcdh-γC5,” “PCDHGC5,” and “protocadherin” found no passage addressing that gene’s role in AD pathogenesis. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Authors
Nativio, R., Donahue, G., Berson, A., Lan, Y., Amlie-Wolf, A., Tuzer, F., Toledo, J. B., Gosai, S. J., Gregory, B. D., Torres, C., Trojanowski, J. Q., Wang, L.-S., Johnson, F. B., Bonini, N. M., & Berger, S. L.
Affiliations
  • University of Pennsylvania (US)
  • Drexel University (US)
Corresponding author
  • Johnson, F. Brad
  • Bonini, Nancy M.
  • Berger, Shelley L.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-03-05
Volume
21
Issue
4
Pages
497-505
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0101-9
PMC
PMC6124498
OpenAlex
W2791286257
Cited by
363
References
14
Citations by year
2026: 41 · 2025: 50 · 2024: 60 · 2023: 45 · 2022: 38 · 2021: 44 · 2020: 29 · 2019: 37 · 2018: 19
FWCI
21.44
Type
journal article
Language
en
Update notices
correction (2018-03-19)
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Pennsylvania
  • National Institutes of Health (4r01ns078283-05, AG 10 124, AG 17586, NS078283, R01-NS078283)
  • National Institute on Aging (P30AG010124, P01AG017586)
  • National Institute of Neurological Disorders and Stroke (R35NS097275, R01-NS078283)
  • National Institute of Environmental Health Sciences (P30ES013508)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
Alzheimer's disease, normal aging, H4K16ac, histone acetylation, chromatin state, epigenetic dysregulation, lateral temporal lobe, age-related neurodegeneration, histone modifications, expression quantitative trait loci, genetic variants, age as risk factor
MeSH terms
Aged, Aging, Alzheimer Disease, Analysis of Variance, Brain, Female, Humans, Male, Middle Aged, Epigenesis, Genetic, Chromatin Immunoprecipitation, Genome-Wide Association Study, Histone Deacetylase 1, Epigenomics

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