Single‐cell landscape of sex‐specific drivers of Alzheimer's disease

INTRODUCTION: We investigated sex-specific gene expression associations with the neuropathology and cognitive manifestation of Alzheimer's disease (AD) leveraging single-nucleus transcriptomic datasets including 2.84 million nuclei from the dorsolateral prefrontal cortex (DLPFC). METHODS: We delineated the full scope of sex-specific transcript associations, differential gene expression, signaling pathway, and cell-cell communication network changes in eight major DLPFC cell types. RESULTS: Nine female-specific associations were identified and replicated, involving ADGRV1, OR3A3, IFI27L1, LYRM1, STAP2, TSTD2, PDYN, and TMEM50B. We observed the preponderance of protective female-specific associations in neurons. Sex-specific genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals that may contribute to female-specific risk of Aβ accumulation were also highlighted. DISCUSSION: Our study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline, with identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies. HIGHLIGHTS: Single-nucleus transcriptomic association analysis identified 2660 sex-specific associations involving 2110 genes with four AD endophenotypes. The majority of female-specific associations link to better endophenotype outcomes were from neurons. Nine female-specific associations were replicated, including ADGRV1 and OR3A3 with Aβ; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive trajectory. Sex-specific effect genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals may play roles in female-specific risk for Aβ accumulation.