Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer’s disease neuropathology
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.
Authors
- Guanhong Miao (ORCID: https://orcid.org/0000-0002-8083-7032)
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Julie A. Schneider (ORCID: https://orcid.org/0000-0002-9482-1752)
- Peng Jin (ORCID: https://orcid.org/0000-0001-6137-6659)
- David Bennett (ORCID: https://orcid.org/0000-0001-5354-152X)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- Jung-Hwa Lim (ORCID: https://orcid.org/0000-0002-9355-5448)
- Jinying Zhao (ORCID: https://orcid.org/0000-0003-3243-2660)
- Jingyun Yang (ORCID: https://orcid.org/0000-0002-3495-3710)
- Tongjun Gu (ORCID: https://orcid.org/0000-0002-8379-0962)
- Hao Wu (ORCID: https://orcid.org/0000-0003-1269-7354)
- Helena Palma‐Gudiel (ORCID: https://orcid.org/0000-0002-4961-8077)
- Francine Grodstein (ORCID: https://orcid.org/0000-0002-2699-7051)
- Cheng Gao (ORCID: https://orcid.org/0000-0002-8867-1591)
- Yujing Li (ORCID: https://orcid.org/0000-0002-4363-2484)
- Ronghua Li (ORCID: https://orcid.org/0000-0002-8282-3232)
- Bing Yao (ORCID: https://orcid.org/0000-0002-3205-8130)
- Lei Yu (ORCID: https://orcid.org/0000-0002-0237-8758)
- Yanling Wang (ORCID: https://orcid.org/0009-0003-0061-9946)
Institutions
- Rush University Medical Center (US)
- Emory University (US)
- University of South Florida (US)
- Columbia University Irving Medical Center (US)
- University of Florida (US)
- Rush University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1038/s41467-025-58159-w
- Citations
- 13
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- National Institute on Aging
- National Institute of Mental Health
- National Institute of Diabetes and Digestive and Kidney Diseases