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. [Abstract copyright: © 2022. The Author(s).]
Original language | English |
---|---|
Article number | 5620 |
Journal | Nature Communications |
Volume | 13 |
Issue number | 1 |
Early online date | 24 Sept 2022 |
DOIs | |
Publication status | E-pub ahead of print - 24 Sept 2022 |
Keywords
- Neurodegenerative Diseases - genetics
- DNA Methylation - genetics
- Epigenesis, Genetic
- Alzheimer Disease - metabolism
- Neurofibrillary Tangles - genetics - metabolism
- Humans