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

Author

Listed:
  • Mabel Seto

    (Massachusetts General Hospital
    Brigham and Women’s Hospital
    Harvard Medical School)

  • Michelle Clifton

    (Vanderbilt University Medical Center)

  • Melisa Lara Gomez

    (Vanderbilt University Medical Center)

  • Gillian Coughlan

    (Massachusetts General Hospital
    Brigham and Women’s Hospital
    Harvard Medical School)

  • Katherine A. Gifford

    (Vanderbilt University Medical Center)

  • Angela L. Jefferson

    (Vanderbilt University Medical Center)

  • Philip L. Jager

    (Columbia University Medical Center)

  • David A. Bennett

    (Rush University Medical Center)

  • Yanling Wang

    (Rush University Medical Center)

  • Lisa L. Barnes

    (Rush University Medical Center)

  • Julie A. Schneider

    (Rush University Medical Center)

  • Timothy J. Hohman

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Rachel F. Buckley

    (Massachusetts General Hospital
    Brigham and Women’s Hospital
    Harvard Medical School
    University of Melbourne)

  • Logan Dumitrescu

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

Abstract

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.

Suggested Citation

  • Mabel Seto & Michelle Clifton & Melisa Lara Gomez & Gillian Coughlan & Katherine A. Gifford & Angela L. Jefferson & Philip L. Jager & David A. Bennett & Yanling Wang & Lisa L. Barnes & Julie A. Schnei, 2025. "Sex-specific associations of gene expression with Alzheimer’s disease neuropathology and ante-mortem cognitive performance," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64525-5
    DOI: 10.1038/s41467-025-64525-5
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