Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease

Using an in silico network-based discovery approach, the authors identified sildenafil as a repurposable drug for Alzheimer's disease. Analyzing insurance claims data from over 7 million individuals, they found that sildenafil usage was associated with a reduced risk of Alzheimer's disease diagnosis. We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and 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 x 10(-8)). Propensity score-stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts tested (diltiazem, glimepiride, losartan and metformin) after adjusting for age, sex, race and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho-tau expression in neuron models derived from induced pluripotent stem cells from patients with AD, supporting mechanistically its potential beneficial effect in AD. The association between sildenafil use and decreased incidence of AD does not establish causality, which will require a randomized controlled trial.

Automated summary

Using a network-based discovery approach, the authors identified sildenafil as a repurposable drug for Alzheimer's disease, and found that its usage was associated with a significantly reduced risk of AD diagnosis. The study also developed a methodology for AD drug repurposing based on endophenotype disease modules, and experimental evidence showed potential beneficial effects of sildenafil on AD.