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<p>The biological mechanisms underlying the increased prevalence of Alzheimer’s disease (AD) in women remain undefined. While previous case/control studies have identified sex-biased molecular pathways, the sex-specific relationships between gene expression and AD endophenotypes, particularly involving sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau, as well as antemortem longitudinal cognition. Among 23,118 significant gene associations, 10% were sex-specific, with 73% of these identified in females and primarily associated with tau tangles and longitudinal cognition (90%). Notably, four X-linked genes, <i>MCF2</i>, <i>HDAC8</i>, <i>FTX</i>, and <i>SLC10A3</i>, demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant <i>sex x gene</i> interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, underscoring the importance of sex-aware analyses to advance precision medicine approaches in AD.</p>

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Sex-specific associations of gene expression with Alzheimer’s disease neuropathology and ante-mortem cognitive performance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Mabel Seto,
  • Michelle Clifton,
  • Melisa Lara Gomez,
  • Gillian Coughlan,
  • Katherine A. Gifford,
  • Angela L. Jefferson,
  • Philip L. De Jager,
  • David A. Bennett,
  • Yanling Wang,
  • Lisa L. Barnes,
  • Julie A. Schneider,
  • Timothy J. Hohman,
  • Rachel F. Buckley,
  • Logan Dumitrescu

摘要

The biological mechanisms underlying the increased prevalence of Alzheimer’s disease (AD) in women remain undefined. While previous case/control studies have identified sex-biased molecular pathways, the sex-specific relationships between gene expression and AD endophenotypes, particularly involving sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau, as well as antemortem longitudinal cognition. Among 23,118 significant gene associations, 10% were sex-specific, with 73% of these identified in females and primarily associated with tau tangles and longitudinal cognition (90%). Notably, four X-linked genes, MCF2, HDAC8, FTX, and SLC10A3, demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant sex x gene interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, underscoring the importance of sex-aware analyses to advance precision medicine approaches in AD.