Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer’s disease neuropathology

Jinying Zhao (), Tongjun Gu, Cheng Gao, Guanhong Miao, Helena Palma-Gudiel, Lei Yu, Jingyun Yang, Yanling Wang, Yujing Li, Junghwa Lim, Ronghua Li, Bing Yao, Hao Wu, Julie A. Schneider, Nicholas Seyfried, Francine Grodstein, Philip L. Jager, Peng Jin () and David A. Bennett ()
Additional contact information
Jinying Zhao: University of South Florida
Tongjun Gu: University of Florida
Cheng Gao: University of South Florida
Guanhong Miao: University of South Florida
Helena Palma-Gudiel: University of Florida
Lei Yu: Rush University Medical Center
Jingyun Yang: Rush University Medical Center
Yanling Wang: Rush University Medical Center
Yujing Li: Emory University School of Medicine
Junghwa Lim: Emory University School of Medicine
Ronghua Li: Emory University School of Medicine
Bing Yao: Emory University School of Medicine
Hao Wu: Emory University School of Public Health
Julie A. Schneider: Rush University Medical Center
Nicholas Seyfried: Emory University School of Medicine
Francine Grodstein: Rush University Medical Center
Philip L. Jager: Columbia University Medical Center
Peng Jin: Emory University School of Medicine
David A. Bennett: Rush University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58159-w

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