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DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types

Lookup NU author(s): Professor Alan ThomasORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s). Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types.

Publication metadata

Author(s): Shireby G, Dempster EL, Policicchio S, Smith RG, Pishva E, Chioza B, Davies JP, Burrage J, Lunnon K, Seiler Vellame D, Love S, Thomas A, Brookes K, Morgan K, Francis P, Hannon E, Mill J

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 24/09/2022

Acceptance date: 13/09/2022

Date deposited: 13/10/2022

ISSN (electronic): 2041-1723

Publisher: Springer Nature


DOI: 10.1038/s41467-022-33394-7

PubMed id: 36153390


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Funder referenceFunder name
Alzheimer’s Society