Sex‐specific associations of gene expression in brain with Alzheimer's disease pathology and cognitive performance.

Background: Alzheimer's disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized. Methods: We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05). Results: Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2). Conclusion: Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation. [ABSTRACT FROM AUTHOR]