Sildenafil (Viagra) is a candidate drug for Alzheimer’s disease

Abstract

AbstractBackgroundThe hypothesis that accumulation of amyloid‐beta protein and consequent tau pathology represents the main cause of Alzheimer’s disease (AD) has dominated the field for more than 2 decades; yet, anti‐tau or anti‐amyloid selective drug discovery approaches have lack of clinical benefits for AD patients. We posited that systematic identification of underlying AD‐related endophenotype modules shared by amyloid and tau may provide a foundation for generating predictive models to characterize pathogenesis and therapeutic development for AD.MethodIn this study, we developed an endophenotype network‐based methodology for in silico drug repurposing in AD. Specifically, we proposed an integrated network‐based framework by incorporating systems pharmacology and network medicine strategies to identify candidate drugs for AD. We further evaluated the drug‐AD outcomes by analyzing 7.23 million U.S. commercially insured individuals and investigated the drug’s mechanism‐of‐action using AD patient‐induced pluripotent stem cells (iPSC)‐derived neuron models.ResultUsing an endophenotype disease module‐based methodology for Alzheimer’s disease (AD) drug repurposing, we identified sildenafil as a potential disease risk modifier. Based on retrospective case‐control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25‐0.39, P<1.0´10−8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho‐tau expression in AD patient iPSC‐derived neurons, supporting mechanistically its potential beneficial effect in Alzheimer’s disease.ConclusionWe identified sildenafil (Viagra) as potential treatment of AD; yet, the association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.