APOE*4 risk-modifying genes and drug targets in Alzheimer's disease through cell-type-specific genomic analyses

INTRODUCTION: Genetics studies can identify drug targets that counteract the effects of the apolipoprotein E ε4 allele (APOE*4) on Alzheimer's disease (AD) but have remained limited in power and crucially did not assess genetic findings with regard to APOE*4's cell-type-specific impact on pathobiology. METHODS: We conducted a novel APOE*4-stratified genome-wide association study (GWAS) of AD (N = 447,669) and integrated results with brain cell-type-specific multi-omics data to identify APOE*4 and cell-type-specific AD genes, followed by compound and drug repurposing. RESULTS: In APOE*4 non-carriers (APOE*4−) and carriers (APOE*4+), we respectively identified 33 and 11 cell type–gene pairs with strong prioritization support. Oligodendrocytes displayed the largest proportion of APOE*4+ genes. Several genes were druggable and pinpointed APOE*4-stratified drugs or compounds. DISCUSSION: We identified a set of APOE*4-stratified genes that may be causal for AD through brain cell-type-specific mechanisms. We additionally identified compounds that may shed light on therapeutic avenues for treating AD based on an individual's APOE*4 status.