Early oligodendrocyte dysfunction signature in Alzheimer’s disease: Insights from DNA methylomics and transcriptomics
8 affiliations
- 1Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
- 2UCL Queen Square Institute of Neurology, London, UK
- 3UCL Queen Square Institute of Neurology
- 4UK Dementia Research Institute, London, UK
- 5Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- 6Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
- 7Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
- 8Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. [email protected]
Abstract
Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altered brain DNA methylation, an epigenetic modification that provides the interplay between genetics and environmental cues to tightly regulate gene expression, is well documented in AD. Yet, cell-type-specific investigations remain limited. Here, we examine the role of DNA methylation and OLGs in AD, and how such changes may impact gene expression. We performed weighted-gene correlation network analysis (WGCNA) on multiple brain omics AD datasets across species: human DNA methylation data from 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We compared AD-associated network modules enriched for OLG genes across AD brain regions, as well as with other neurodegenerative disease DNA methylation datasets. We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions representing early and late AD pathology stages. Genes within this signature showed altered expression in AD OLGs, confirming cell-type specificity and relevance to AD. This OLG signature was also preserved in transgenic mice with early Aβ pathology and in other neurodegenerative diseases without Aβ pathology. We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings highlight OLG-associated DNA methylation changes as important in AD pathogenesis, and possibly in other neurodegenerative diseases, opening new avenues for therapeutic development.
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BibTeX
@article{fodder2026early,
title = {{Early oligodendrocyte dysfunction signature in Alzheimer’s disease: Insights from DNA methylomics and transcriptomics}},
author = {Katherine Fodder and Hannah M. G. Smith and Ümran Yaman and Ignazio Stefano Piras and Megha N. Murthy and John Hardy and Tammaryn Lashley and Rohan de Silva and Dervis A. M. Salih and Conceição Bettencourt},
journal = {Molecular Psychiatry},
year = {2026},
month = jun,
doi = {10.1038/s41380-026-03686-1},
url = {https://doi.org/10.1038/s41380-026-03686-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Early oligodendrocyte dysfunction signature in Alzheimer’s disease: Insights from DNA methylomics and transcriptomics
AU - Katherine Fodder
AU - Hannah M. G. Smith
AU - Ümran Yaman
AU - Ignazio Stefano Piras
AU - Megha N. Murthy
AU - John Hardy
AU - Tammaryn Lashley
AU - Rohan de Silva
AU - Dervis A. M. Salih
AU - Conceição Bettencourt
PY - 2026
DA - 2026/06/18
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03686-1
UR - https://doi.org/10.1038/s41380-026-03686-1
AB - Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altered brain DNA methylation, an epigenetic modification that provides the interplay between genetics and environmental cues to tightly regulate gene expression, is well documented in AD. Yet, cell-type-specific investigations remain limited. Here, we examine the role of DNA methylation and OLGs in AD, and how such changes may impact gene expression. We performed weighted-gene correlation network analysis (WGCNA) on multiple brain omics AD datasets across species: human DNA methylation data from 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We compared AD-associated network modules enriched for OLG genes across AD brain regions, as well as with other neurodegenerative disease DNA methylation datasets. We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions representing early and late AD pathology stages. Genes within this signature showed altered expression in AD OLGs, confirming cell-type specificity and relevance to AD. This OLG signature was also preserved in transgenic mice with early Aβ pathology and in other neurodegenerative diseases without Aβ pathology. We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings highlight OLG-associated DNA methylation changes as important in AD pathogenesis, and possibly in other neurodegenerative diseases, opening new avenues for therapeutic development.
SN - 1359-4184
SN - 1476-5578
ER -