Sex- and APOE-specific transcriptomic drug repurposing identifies four candidate therapeutics for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) risk is strongly modified by biological sex and apolipoprotein E (APOE) genotype, yet these factors are rarely incorporated into drug discovery efforts. We hypothesized that sex- and APOE-specific transcriptomic signatures define distinct molecular endotypes of AD which can be therapeutically targeted through precision drug repurposing using an integrative data framework. METHODS: We analyzed frontal cortex RNA sequencing data from 369 individuals in the Religious Orders Study Rush Memory and Aging Project cohort (APOE ε3/ε3 and APOE ε3/ε4) to derive sex- and genotype-specific AD gene expression signatures. Differential expression and Gene Ontology enrichment analyses identified biological processes uniquely or differentially perturbed across groups. Drug-induced perturbation signatures from the Library of Integrated Network-Based Cellular Signatures database were queried to identify US Food and Drug Administration-approved compounds predicted to reverse AD-associated signatures. Top candidates were validated using the PearlDiver-Mariner claims database to assess AD risk associations. RESULTS: Transcriptomic dysregulation varied markedly across groups. Female APOE ε3/ε3 AD brains exhibited the greatest number of differentially expressed genes (n = 8903), whereas male APOE ε3/ε3 showed the fewest (n = 640). APOE ε4 carriers demonstrated enrichment of immune and inflammatory pathways, including cytokine signaling and extracellular signal-regulated kinase cascade activation, whereas APOE ε3/ε3 groups exhibited downregulation of synaptic organization, vesicle trafficking, and bioenergetic processes. Drug reversal analysis identified four candidates: riluzole, chloroquine, acetazolamide, and anagrelide. In population-level validation, riluzole (relative risk [RR] = 0.52; 95% confidence interval [CI]: 0.40-0.68), chloroquine (RR = 0.56; 95% CI: 0.55-0.58), and acetazolamide (RR = 0.76, 95% CI: 0.73-0.79) were associated with significantly reduced AD risk, whereas anagrelide exhibited increased risk. Protective associations for riluzole, chloroquine, and acetazolamide held in both sexes, with stronger effects in women. DISCUSSION: Sex and APOE genotype define biologically distinct AD transcriptomic states, with subgroup-specific and shared pharmacologic reversibility. Integrating stratified transcriptomics with population-scale validation identified clinically actionable candidates supporting an AD precision drug repurposing framework.