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. [Abstract copyright: © 2022. The Author(s).]
Original languageEnglish
Article number5620
JournalNature Communications
Issue number1
Early online date24 Sept 2022
Publication statusE-pub ahead of print - 24 Sept 2022


  • Neurodegenerative Diseases - genetics
  • DNA Methylation - genetics
  • Epigenesis, Genetic
  • Alzheimer Disease - metabolism
  • Neurofibrillary Tangles - genetics - metabolism
  • Humans


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