Abstract
BackgroundEvidence from observational studies and randomized controlled trials (RCTs) remains discordant on the impact of statin therapy on long-term outcomes related to Alzheimer's disease. Observational studies find relatively large effect sizes; RCTs fail to demonstrate cognitive benefits. Methodological limitations in both approaches may explain the disconnect.ObjectiveTo bridge the gap between observational and RCT studies, this study uses Real World Data (RWD) to evaluate the association between statin use and incident AD risk, and contributes additional detailed stratification by statin type and dosage.MethodsThis observational analysis of EHR data from over 125 million U.S. patients through the TriNetX platform compared statin exposure in adults over 45 years old with a diagnosis of dyslipidemia, and no prior AD diagnosis, controlling for demographics, a range of known comorbidities, laboratory values, and medications. Primary outcomes were incident AD, other degenerative neurological diseases, and all-cause mortality. Sub-analyses compared risks by statin type and dosage.ResultsStatin exposure was associated with a substantially lower risk of incident AD compared with non-exposure (RR = 0.69), similar to meta analyses of observational studies. Lipophilic and hydrophilic statins showed reduced AD risk compared to controls; hydrophilic statins showed a slightly greater protective effect. High-dose and low/medium-dose statins conferred similar risk reductions with no significant dose-dependent difference.ConclusionsOur findings provide evidence that statin therapy is associated with reduced risk of AD and related outcomes, extending prior observational data with broader population representation and rigorous confounder control. Pending further evidence, statins may be considered as part of comprehensive strategies to reduce AD risk.