# 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.

## Key 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.