*4 Risk-Modifying Genes and Drug Targets in Alzheimer's Disease through Cell-Type Specific Genomic Analyses.

Résumé

IMPORTANCE: *4 is the strongest, common genetic risk factor for late-onset Alzheimer's disease (AD) with widespread and cell-type-specific impact on disease pathogenesis. Genetics and omics studies can help identify genes that counteract the effects of *4, but so far have remained relatively small and crucially did not assess genetic findings through a cell-type-specific framework.OBJECTIVES: Perform a large-scale *4 stratified genome-wide association study (GWAS) of AD integrated with genetically tethered cell-type-specific multi-omics data.DESIGN: Meta-analysis of *4 stratified AD GWAS in case-control, family-based, population-based, and longitudinal AD-related cohorts from the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, and UK Biobank. Integration of GWAS with brain cell-type-specific genetic regulation of gene expression data, from the Religious Orders Study and Memory and Aging Project, to identify *4 and cell-type-specific AD genes. Cell-type-specific multi-omics gene prioritization followed by compound and drug repurposing. Data analyzed between January 2023 and September 2025.SETTING: Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Single-nucleus (sn) RNA-seq data from dorsolateral prefrontal cortex.PARTICIPANTS: 567,521 eligible participants for AD genetic association studies were selected from referred and volunteer samples, of which 119,852 were excluded for analysis exclusion criteria.MAIN OUTCOME AND MEASURES: *4 and cell-type-specific gene Z-scores and FDR-corrected P-values. Gene prioritization scores and *4 stratified enriched compounds.RESULTS: 67 and 17 significant cell-type-gene pairs were identified in *4 non-carriers (*4-) and carriers (*4+) respectively. Oligodendrocytes displayed the largest proportion of *4+ genes. 46 cell-type-gene pairs were supported by at least half of the gene prioritization analyses. Several prioritized genes were druggable and displayed enrichment of *4 stratified drugs or compounds. Top *4+ genes with connections to enriched drugs or compounds included (astrocytes), and (oligodendrocytes), and (excitatory neurons).CONCLUSION AND RELEVANCE: We identified a set of *4 stratified genes that may be causal for AD through brain cell-type-specific mechanisms and prioritized top genes for further interrogation. We additionally identified compounds that may be repurposed or shed light on therapeutic avenues for treating AD based on an individual's *4 status. Top identified compounds such as Hydrocortisone and Trolox implicate oxidative stress and neuroinflammation as potential biological targets in *4+ individuals.