Brain single-cell transcriptome-informed Mendelian randomization identifies potential druggable therapeutic targets for Alzheimer's disease
Renjun Huang, Liqing Guan, Yang Chen, Qiang Jiao, Weirong Yin, Haixia ZhouBackground
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, accounting for 60–70% of all dementia cases. The limitations of current therapies and the complexity of its multifaceted pathological mechanisms underscore the urgent need to identify candidate therapeutic targets.
Objective
This study aims to systematically identify brain cell type-specific candidate druggable targets for Alzheimer's disease by integrating brain single-cell expression quantitative trait loci (sc-eQTL) data with large-scale genome-wide association studies (GWAS) using Mendelian randomization (MR) and colocalization analysis.
Methods
This study integrates sc-eQTL data with large-scale GWAS to systematically assess the causal relationships between gene expression in eight brain cell types and AD risk using MR analysis and colocalization analysis. Target functionality was further analyzed through KEGG pathway analysis and the STRING protein interaction network.
Results
MR analysis prioritized 46 genetically supported candidate druggable genes (FDR < 0.05), of which 10 gene–cell type pairs corresponding to 9 unique genes showed colocalization support. Cell type-specific analysis suggested that these genetically supported associations were restricted to specific brain cell types. Protein–protein interaction analysis with clinical AD drug targets showed that 13% of the candidate targets (6/46) had direct network connections with approved AD drug targets, suggesting potential pharmacological relevance.
Conclusions
This study provides a brain cell type-resolved genetic prioritization framework for AD, nominating genetically supported candidate druggable targets and linking them to neurodegenerative and immune-related pathways. This framework may help generate hypotheses for future experimental validation and drug development.