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

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.

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.

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.

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.