Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real‐World Data Screening and in Vitro Validation

ABSTRACT

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‐world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large‐scale Japanese claims database ( n  = 2,090,465; 2005–2023). We identified patients newly prescribed a study drug and applied an active‐comparator, new‐user design. We used propensity score‐based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD‐10 codes (F00 and G30). We estimated cumulative incidence using IPTW‐adjusted Kaplan–Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine–Gray competing risk models, empirical calibration with negative control outcomes, and E‐value estimation. We performed in vitro validation using Aβ‐Tet‐ON SH‐SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41–0.71, p  < 0.05 post‐FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH‐SY5Y cells in a dose‐dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD‐based pharmacoepidemiology and in vitro 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.