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<p>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 <i>RIN3, PLCG2, ITGA2B</i>, and <i>USP6NL</i>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • 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. De Jager,
  • Peng Jin,
  • David A. Bennett

摘要

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.