Fine-mapping and replication of EWAS loci harboring putative epigenetic alterations associated with AD neuropathology in a large collection of human brain tissue samples

Alzheimers Dement. 2023 Apr;19(4):1216-1226. doi: 10.1002/alz.12761. Epub 2022 Aug 12.


Introduction: Our previous epigenome-wide association study (EWAS) of Alzheimer's disease (AD) in human brain identified 71 CpGs associated with AD pathology. However, due to low coverage of the Illumina platform, many important CpGs might have been missed.

Methods: In a large collection of human brain tissue samples (N = 864), we fine-mapped previous EWAS loci by targeted bisulfite sequencing and examined their associations with AD neuropathology. DNA methylation was also linked to gene expression of the same brain cortex.

Results: Our targeted sequencing captured 130 CpGs (∼1.2 kb), 93 of which are novel. Of the 130 CpGs, 57 sites (only 17 included in previous EWAS) and 12 gene regions (e.g., ANK1, BIN1, RHBDF2, SPG7, PODXL) were significantly associated with amyloid load. DNA methylation in some regions was associated with expression of nearby genes.

Discussion: Targeted methylation sequencing can validate previous EWAS loci and discover novel CpGs associated with AD pathology.

Keywords: AD neuropathology; Alzheimer's disease; brain DNA methylation; targeted bisulfite sequencing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Brain / pathology
  • DNA Methylation
  • Epigenesis, Genetic
  • Epigenome
  • Genome-Wide Association Study
  • Humans