Seto Mabel, Clifton Michelle, Gomez Melisa Lara, Coughlan Gillian, Gifford Katherine A, Jefferson Angela L, De Jager Philip L, Bennett David A, Wang Yanling, Barnes Lisa L, Schneider Julie A, Hohman Timothy J, Buckley Rachel F, Dumitrescu Logan
Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
bioRxiv. 2025 Jan 2:2025.01.02.631098. doi: 10.1101/2025.01.02.631098.
The biological mechanisms underlying women's increased Alzheimer's disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly 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. Of 23,118 significant gene associations, 10% were significant in one sex and not the other (sex-specific). Most sex-specific gene associations were identified in females (73%) and associated with tau tangles and longitudinal cognition (90%). Four X-linked genes, , , , and , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, reinforcing the potential for sex-aware analyses to enhance precision medicine approaches in AD.
女性阿尔茨海默病（AD）患病率增加背后的生物学机制尚不清楚。以往的病例/对照研究已经确定了性别偏向的分子途径，但基因表达与AD内表型之间的性别特异性关系，尤其是性染色体，尚未得到充分探索。利用来自767名死者3个脑区的大量转录组数据，我们研究了基因表达与死后β-淀粉样蛋白和tau以及生前纵向认知之间的性别特异性关联。在23118个显著的基因关联中，10%在一种性别中显著而在另一种性别中不显著（性别特异性）。大多数性别特异性基因关联在女性中被发现（73%），并与tau缠结和纵向认知相关（90%）。四个X连锁基因，即 、 、 和 ，在与AD内表型的关联中表现出显著的性别差异（即显著的 相互作用）。我们的结果还揭示了性别特异性的生物学途径，包括神经炎症和神经元发育在女性中的特定作用，这加强了性别意识分析在提高AD精准医学方法方面的潜力。
