Screening of cell-type-specific meta-programs for drug repurposing in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex cellular changes. To identify transcriptional signatures involved in AD pathology, we first analyzed nine single-cell/nucleus RNA-seq datasets from 67 high-pathology cases (Braak stages V/VI), generating an atlas of 363 243 cells. Using a multi-sample integration strategy, we identified 51 cross-sample meta-programs (MPs) across seven cell types that collectively capture key AD-related processes, including synaptic dysfunction and neuroinflammation. By screening bulk transcriptomes from 1208 ad and 725 normal samples, we found that 26 MPs (13 pathogenic and 13 protective) displayed differential activity in AD, characterized by up-regulation of microglia MPs and down-regulated of neuron MPs. Furthermore, spatial transcriptomics revealed that these MPs form spatially coherent communities associated with distinct cellular neighborhoods. Finally, we performed an integrative drug repurposing screen to identify candidate drugs predicted to regulate pathogenic MPs. In conclusion, we conducted an integrated multi-omics study to identify AD cell-type-specific MPs, and this framework can be applied to deconvolve cellular heterogeneity and screen candidate drugs for AD.