Sex-specific Associations of Gene Expression with Alzheimer’s Disease Neuropathology and Ante-mortem Cognitive Performance

TL;DR

This study explores how gene expression relates to Alzheimer’s disease in men and women, finding sex-specific patterns that could help improve precision medicine for the disease.

Contribution

The study identifies sex-specific gene associations with Alzheimer’s disease neuropathology and cognition, including significant X-linked genes and biological pathways.

Findings

10% of significant gene associations with Alzheimer’s disease were sex-specific, with 73% found in females.

Four X-linked genes showed significant sex differences in their associations with AD endophenotypes.

Female-specific pathways like neuroinflammation and neuronal development were linked to Alzheimer’s disease.

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 × 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.

Figures