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

Fang, J., Zhang, P., Zhou, Y., et al. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease. Nut Aging (2021). https://doi.org/10.1038/s43587-021-00138-z

Commentary

An endophenotypic disease module-based methodology for drug repositioning for Alzheimer's disease (AD) has been developed and sildenafil has been identified as a potential disease risk modifier.

This is based on a retrospective case-control pharmacoepidemiological analysis of claims data from 7.23 million people, suggesting that sildenafil use is significantly associated with a 69% reduction in the risk of AD. (Hazard ratio 0.31, 95% confidence interval 0.25-0.39, P <1.0 × 10-8)

Furthermore, propensity score stratification analysis also confirmed that sildenafil was significantly associated with a reduced risk of AD in all four drug cohorts tested (diltiazem, glimepiride, losartan, and metformin), adjusting for age, gender, race, and comorbidities.

And sildenafil has also been found to increase neurite outgrowth and decrease phospho-tau expression in a neuron model derived from pluripotent stem cells of AD patients, supporting its potential beneficial effects in AD.

However, the association between the use of sildenafil and reduced incidence of AD has not been established as causal, and it has been stated that randomized controlled trials are needed.