Journal Article

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

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

2025

Overview

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. The genetic basis of sex differences in Alzheimer’s disease (AD) is not well characterized. Here, authors report 2,320 sex-specific gene associations with 3 AD endophenotypes using bulk RNAseq data from 3 brain regions in ROS/MAP.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/91 / 631/378/1689/1283 / 631/378/2583 / Aged / Aged, 80 and over / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Autopsy / Brain / Brain - metabolism / Brain - pathology / Chromosomes / Cognition / Cognition & reasoning / Cognition - physiology / Cognitive ability / Female / Females / Gender differences / Gene expression / Genes, X-Linked / Humanities and Social Sciences / Humans / Male / Middle Aged / multidisciplinary / Neurodegenerative diseases / Precision medicine / Science / Science (multidisciplinary) / Sex Characteristics / Sex chromosomes / Sex differences / Sex Factors / Symporters - genetics / Tau protein / tau Proteins - genetics / tau Proteins - metabolism / Transcriptome / Transcriptomics / β-Amyloid