{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T13:04:04Z","timestamp":1784379844883,"version":"3.55.0"},"reference-count":62,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real\u2010world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large\u2010scale Japanese claims database (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092,090,465; 2005\u20132023). We identified patients newly prescribed a study drug and applied an active\u2010comparator, new\u2010user design. We used propensity score\u2010based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD\u201010 codes (F00 and G30). We estimated cumulative incidence using IPTW\u2010adjusted Kaplan\u2013Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine\u2013Gray competing risk models, empirical calibration with negative control outcomes, and E\u2010value estimation. We performed in\u00a0vitro validation using A\u03b2\u2010Tet\u2010ON SH\u2010SY5Y cells and quantified A\u03b2 expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41\u20130.71,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05 post\u2010FDR correction); this association remained robust across sensitivity analyses. In\u00a0vitro, benzbromarone reduced A\u03b2 protein expression in SH\u2010SY5Y cells in a dose\u2010dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD\u2010based pharmacoepidemiology and in\u00a0vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.\n                  <\/jats:p>","DOI":"10.1111\/cts.70650","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T05:16:29Z","timestamp":1782105389000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real\u2010World Data Screening and in Vitro Validation"],"prefix":"10.1111","volume":"19","author":[{"given":"Sho","family":"Sakagami","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisei","family":"Kumamoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimpei","family":"Kawano","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Fukuoka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanami","family":"Ino","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9146-8554","authenticated-orcid":false,"given":"Kengo","family":"Hamamura","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigehiro","family":"Ohdo","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0004-4535","authenticated-orcid":false,"given":"Naoya","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.53275"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40290-025-00558-x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1166"},{"key":"e_1_2_8_5_1","unstructured":"Biotechnology Innovation Organization (BIO) Quantitative Life Sciences (QLS) Informa Pharma Intelligence \u201cClinical development success rates 2011\u20132020 \u201daccessed October 8 2025 Clinical Development Success Rates and Contributing Factors 2011\u20132020 PDF."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12980"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2022.0068"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2022-071108","article-title":"Target Trial Emulation: Applying Principles of Randomised Trials to Observational Studies","volume":"39","author":"Matthews A. 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