Sildenafil was found to significantly reduce the risk for Alzheimer disease (AD) and may be a potential disease modifying drug, according to results of a drug repurposing network analysis and retrospective case control study published in Nature Aging.
An AD endophenotype model was made using data from large-scale amyloid or tauopathy genome-wide association studies. Drugs approved by the United States Food and Drug Administration (FDA) were evaluated for their effect on the AD endophenotype. To confirm potential efficacy for drugs on AD, data were sourced from the MarketScan Medicare Claims database. Patients who had been exposed to candidate drugs were matched with unexposed individuals and assessed for AD diagnoses between 2012 and 2017.
AD seed genes were significantly enriched for 13 gene sets related to amyloidosis or tauopathy (all P ≤2.59×10-3). Out of 144 seed genes, 102 were connected through the human interactome (P <.001).
Drugs approved by the US FDA were assessed for how they would affect the AD endophenotype module. The top 100 drugs were selected and grouped by Anatomical Therapeutic Chemical Classification. Among these drugs, 66 had evidence of crossing the blood-brain barrier. The investigators selected the drug sildenafil for further testing.
Data from 7.23 million individuals with commercially available insurance in the US were assessed for sildenafil exposure. A total of 116,412 sildenafil users were matched with 460,356 unexposed individuals, 251,360 diltiazem users, 664,265 losartan users, 159,597 glimepiride users, and 723,082 metformin users.
After 6 years of sildenafil use, the risk for AD was reduced by 69% compared with nonsildenafil users (hazard ratio [HR], 0.31; 95% CI, 0.25-0.39; P <1×10-8). Sildenafil reduced risk for AD by 65% compared with diltiazem (HR, 0.35; 95% CI, 0.29-0.44; P <1×10-8), by 55% compared with losartan (HR, 0.45; 95% CI, 0.35-0.55; P <1×10-8), by 64% compared with glimepiride (HR, 0.36; 95% CI, 0.28-0.45; P <1×10-8), and by 63% compared with metformin (HR, 0.37; 95% CI, 0.30-0.45; P <1×10-8).
Using in vitro experiments, pretreating cells with 100 μM sildenafil reduced phosphorylated glycogen synthase kinase 3ß (GSK3ß; P =.023) and cyclin-dependent kinase 5 (CDK5; P =.008). Using induced pluripotent stem cells derived from patients with AD, cells that were treated with sildenafil had elevated neurite growth and reduced accumulation of phosphorylated tau181.
These findings may have been limited by the fact that clinical information was not available for these patients. In addition, there was no information available about apolipoprotein E status.
This study used an integrated, network-based approach for drug repurposing discovery. Additional study is needed to assess whether sildenafil may be an effective disease-modifying agent for AD.
Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of disclosures.
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. Nat Aging. 2021;1:1175-1188. doi:10.1038/s43587-021-00138-z