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

Gemma Shireby, Emma L. Dempster, Stefania Policicchio, Rebecca G. Smith, Ehsan Pishva, Barry Chioza, Jonathan P. Davies, Joe Burrage, Katie Lunnon, Dorothea Seiler Vellame, Seth Love, Alan Thomas, Keeley Brookes, Kevin Morgan, Paul Francis, Eilis Hannon and Jonathan Mill ()
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Gemma Shireby: University of Exeter Medical School, University of Exeter
Emma L. Dempster: University of Exeter Medical School, University of Exeter
Stefania Policicchio: University of Exeter Medical School, University of Exeter
Rebecca G. Smith: University of Exeter Medical School, University of Exeter
Ehsan Pishva: Maastricht University
Barry Chioza: University of Exeter Medical School, University of Exeter
Jonathan P. Davies: University of Exeter Medical School, University of Exeter
Joe Burrage: University of Exeter Medical School, University of Exeter
Katie Lunnon: University of Exeter Medical School, University of Exeter
Dorothea Seiler Vellame: University of Exeter Medical School, University of Exeter
Seth Love: University of Bristol Medical School (Translational Health Sciences)
Alan Thomas: Newcastle University
Keeley Brookes: Nottingham Trent University
Kevin Morgan: University of Nottingham
Paul Francis: University of Exeter Medical School, University of Exeter
Eilis Hannon: University of Exeter Medical School, University of Exeter
Jonathan Mill: University of Exeter Medical School, University of Exeter

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33394-7

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