Sex-Dependent Molecular Landscape of Alzheimer's Disease Revealed by Large-Scale Single-Cell Transcriptomics

INTRODUCTION: Alzheimer's disease (AD) shows significant sex differences in prevalence and clinical manifestations, but the underlying molecular mechanisms remain unclear.

METHODS: This study uses a large-scale single-cell transcriptomic atlas of the human prefrontal cortex to investigate sex-dependent molecular changes in AD. Our approach combined cell type-specific and sex-specific differential gene expression analysis, pathway enrichment, gene regulatory network construction and cell-cell communication analysis to identify sex-dependent changes.

RESULTS: We found significant sex-specific gene expression patterns and pathway alterations in AD. Male astrocytes showed changes in cell death pathways, with RPTOR as a key regulator, while female astrocytes had alterations in Wnt signaling and cell cycle regulation. Cell-cell communication analysis uncovered sex-specific intercellular signaling patterns, with male-specific impacts on apoptosis-related signaling and female-specific alterations in Wnt and calcium signaling.

DISCUSSION: This study reveals sex-dependent gene expression patterns, pathway alterations, and intercellular communication changes, suggesting the need for sex-specific approaches in AD research.