Sex-specific Associations of Gene Expression with Alzheimer's Disease Neuropathology and Ante-mortem Cognitive Performance.
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Abstract | 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. |
Year of Publication | 2025
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Journal | bioRxiv : the preprint server for biology
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Date Published | 01/2025
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ISSN | 2692-8205
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DOI | 10.1101/2025.01.02.631098
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PubMed ID | 39803447
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