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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Nic, 2025. "Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer’s disease neuropathology," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58159-w
    DOI: 10.1038/s41467-025-58159-w
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