{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:56:41Z","timestamp":1791943001077,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":52,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Alzheimer's disease (AD) risk is strongly modified by biological sex and apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ) genotype, yet these factors are rarely incorporated into drug discovery efforts. We hypothesized that sex\u2010 and\n                      <jats:italic>APOE<\/jats:italic>\n                      \u2010specific transcriptomic signatures define distinct molecular endotypes of AD which can be therapeutically targeted through precision drug repurposing using an integrative data framework.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed frontal cortex RNA sequencing data from 369 individuals in the Religious Orders Study Rush Memory and Aging Project cohort (\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b53\/\u03b53 and\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b53\/\u03b54) to derive sex\u2010 and genotype\u2010specific AD gene expression signatures. Differential expression and Gene Ontology enrichment analyses identified biological processes uniquely or differentially perturbed across groups. Drug\u2010induced perturbation signatures from the Library of Integrated Network\u2010Based Cellular Signatures database were queried to identify US Food and Drug Administration\u2013approved compounds predicted to reverse AD\u2010associated signatures. Top candidates were validated using the PearlDiver\u2010Mariner claims database to assess AD risk associations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptomic dysregulation varied markedly across groups. Female\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b53\/\u03b53 AD brains exhibited the greatest number of differentially expressed genes (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a08903), whereas male\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b53\/\u03b53 showed the fewest (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0640).\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 carriers demonstrated enrichment of immune and inflammatory pathways, including cytokine signaling and extracellular signal\u2010regulated kinase cascade activation, whereas\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b53\/\u03b53 groups exhibited downregulation of synaptic organization, vesicle trafficking, and bioenergetic processes. Drug reversal analysis identified four candidates: riluzole, chloroquine, acetazolamide, and anagrelide. In population\u2010level validation, riluzole (relative risk [RR]\u00a0=\u00a00.52; 95% confidence interval [CI]: 0.40\u20130.68), chloroquine (RR\u00a0=\u00a00.56; 95% CI: 0.55\u20130.58), and acetazolamide (RR\u00a0=\u00a00.76, 95% CI: 0.73\u20130.79) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Sex and\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype define biologically distinct AD transcriptomic states, with subgroup\u2010specific and shared pharmacologic reversibility. Integrating stratified transcriptomics with population\u2010scale validation identified clinically actionable candidates supporting an AD precision drug repurposing framework.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70303","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T08:29:06Z","timestamp":1787387346000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex\u2010 and\n                    <i>APOE<\/i>\n                    \u2010specific transcriptomic drug repurposing identifies four candidate therapeutics for Alzheimer's disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2916-6402","authenticated-orcid":false,"given":"Francesca","family":"Vitali","sequence":"first","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona  Tucson Arizona 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Torrandell\u2010Haro","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerson D.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona  Tucson Arizona USA"},{"name":"Department of Neurology, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science University of Arizona  Tucson Arizona USA"},{"name":"Department of Pharmacology, College of Medicine University of Arizona  Tucson Arizona 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