Faculty Collaboration Database

Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer's disease neuropathology. Nat Commun 2025 Mar 22;16(1):2842

Date

03/23/2025

Pubmed ID

40121201

Pubmed Central ID

PMC11929800

DOI

10.1038/s41467-025-58159-w

Scopus ID

2-s2.0-105000708928 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

5-hydroxymethylcytosine, also known as the sixth DNA base of the genome, plays an important role in brain aging and neurological disorders such as Alzheimer's disease. However, little is known about its genome-wide distribution and its association with Alzheimer's disease pathology. Here, we report a genome-wide profiling of 5-hydroxymethylcytosine in 1079 autopsied brains (dorsolateral prefrontal cortex) of older individuals and assess its association with multiple measures of Alzheimer's disease pathologies, including pathological diagnosis of Alzheimer's disease, amyloid-β load, and PHFtau tangle density. Of 197,765 5-hydroxymethylcytosine regions detected, we identified 2821 differentially hydroxymethylated regions associated with Alzheimer's disease neuropathology after controlling for multiple testing and covariates. Many differentially hydroxymethylated regions are located within known Alzheimer's disease loci, such as RIN3, PLCG2, ITGA2B, and USP6NL. Integrative multi-omics analyses support a potential mechanistic role of 5-hydroxymethylcytosine alterations in Alzheimer's disease. Our study presents a large-scale genome-wide atlas of 5-hydroxymethylcytosine in Alzheimer's brain and offers insight into the mechanism underlying Alzheimer's disease pathogenesis.

Author List

Zhao J, Gu T, Gao C, Miao G, Palma-Gudiel H, Yu L, Yang J, Wang Y, Li Y, Lim J, Li R, Yao B, Wu H, Schneider JA, Seyfried N, Grodstein F, De Jager PL, Jin P, Bennett DA

Author

Tongjun Gu PhD Associate Investigator in the Hematopoiesis & Stem Cell Biology department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

5-Methylcytosine
Aged
Aged, 80 and over
Alzheimer Disease
Amyloid beta-Peptides
Brain
DNA Methylation
Female
Genome-Wide Association Study
Humans
Male
Prefrontal Cortex