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Cited by 6Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchEpigenetics and DNA Methylation

Integrative epigenomic landscape of Alzheimer’s Disease brains reveals oligodendrocyte molecular perturbations associated with tau

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Oatman, Stephanie R., Reddy, Joseph S., Atashgaran, Amin, Wang, Xue, Min, Yuhao, Quicksall, Zachary, Vanelderen, Floor, Carrasquillo, Minerva M. +12 more·2026·Nature Communications
DOI 10.1038/s41467-026-68864-9PMC PMC12957399
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Abstract

Abstract Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that are highly variable across individuals. Capturing epigenetic factors that associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 AD brains with neuropathologic measures (Braak stage, Thal phase, and cerebral amyloid angiopathy score) and brain biochemical levels of five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, and p-tau) core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identified 5,478 significant associations, 99.7% of which were with brain tau biochemical measures. Of the tau-associated rCpGms, 93 had concordant associations in external datasets comprising 1,337 brain samples. Integrative transcriptome-methylome analyses uncovered 535 significant gene expression associations for these 93 rCpGms. Genes with concurrent transcriptome-methylome perturbations were enriched in oligodendrocyte marker genes, including known AD risk genes such as BIN1 , myelination genes MYRF, MBP and MAG previously implicated in AD, as well as novel genes like LDB3 . We further annotated the top oligodendrocyte genes in an additional 6 brain single cell and 2 bulk transcriptome datasets from AD and two other tauopathies, Pick’s disease and progressive supranuclear palsy (PSP). Our findings support consistent rCpGm and gene expression associations with these tauopathies and tau-related phenotypes in both bulk brain tissue and oligodendrocyte clusters. In summary, we uncover the integrative epigenomic landscape of AD and demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across different tauopathies.

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  • Tau neuropathology correlates with hypermethylation of oligodendrocyte genes, leading to reduced expression and demyelination.

    “Notably, recent work has shown that tau neuropathology correlates with hypermethylation of oligodendrocyte genes, leading to reduced expression and demyelination [146]; several of the downregulated genes were recovered in our datasets (Shank1, Clmn, Camk1d, Mbp, and Agap1), further supporting the link of oligodendrocyte function restoration with endogenous tau removal.”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [146]

    The Results and Discussion (page numbers not provided) report an association between tau pathology and hypermethylation near oligodendrocyte genes, alongside lower expression of many of those genes. They present the progression to dysmyelination as a possible model, not an established causal sequence; the Discussion says functional studies are needed to determine the order of events. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Oatman, S. R., Reddy, J. S., Atashgaran, A., Wang, X., Min, Y., Quicksall, Z., Vanelderen, F., Carrasquillo, M. M., Liu, C.-C., Yamazaki, Y., Nguyen, T. T., Heckman, M., Zhao, N., DeTure, M., Murray, M. E., Bu, G., Kanekiyo, T., Dickson, D. W., Allen, M., & Ertekin-Taner, N.
Affiliations
  • Mayo Clinic in Florida (US)
  • Mayo Clinic (US)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-03-03
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-68864-9
PMC
PMC12957399
OpenAlex
W7133360275
Cited by
6
References
26
Citations by year
2026: 4 · 2025: 2
FWCI
18.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1 AG051504, U01 AG046139, R01 AG061796, U19 AG074879, P50AG016574, R37AG027924)
  • Cure Alzheimer's Fund
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, DNA methylation, epigenome-wide association study, tau protein, oligodendrocytes, BIN1, MYRF, MBP, metagenome-assembled genomes, LDB3, tauopathy, brain neuropathology

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