Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.
Level 3 - non-randomized controlled study
Retrospective propensity score-stratified cohort study using claims data combined with in vitro preclinical assays.
PubMed 35572351 · doi:10.1038/s43587-021-00138-z
What was done
Researchers applied an in silico network endophenotype disease-module approach to screen candidate drugs for Alzheimer's disease (AD) repurposing, identifying sildenafil. They then conducted a retrospective pharmacoepidemiologic analysis of insurance claims data covering 7.23 million individuals, utilizing propensity score-stratified analyses comparing sildenafil users to four active comparator drug cohorts (diltiazem, glimepiride, losartan, metformin) adjusting for age, sex, race, and comorbidities. In vitro mechanistic assays were performed using AD patient-induced pluripotent stem cell (iPSC)-derived neurons.
What was found
Sildenafil use was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% CI 0.25-0.39, P < 1.0 × 10^-8). This decreased risk remained consistent across all four comparator cohorts. In iPSC-derived neuron models, sildenafil increased neurite growth and decreased phospho-tau expression.
Why it matters
This study identifies sildenafil as a potential repurposing candidate for reducing AD risk using large-scale real-world data paired with cellular mechanistic evidence. It establishes a strong rationale for testing sildenafil in prospective randomized clinical trials.
Limits
The clinical analysis relies entirely on observational claims data, which cannot establish causality and remains susceptible to unmeasured confounding, coding inaccuracies, and confounding by indication. Mechanistic support is limited to in vitro stem cell models.
Cited by
- supports An in silico study analyzing over 6 million patient records found that individuals who used sildenafil (Viagra) had about a 60% reduced risk of developing Alzheimer's disease.