Using the computational methodology, scientists- in a new Cleveland Clinic-led study- screened and validated FDA-approved drugs as potential therapies for Alzheimer’s disease. This large-scale analysis found that Sildenafil is a promising drug candidate to help prevent and treat Alzheimer’s disease.
Sildenafil is an FDA-approved therapy for erectile dysfunction (Viagra) and pulmonary hypertension (Ravatio).
The analysis contains a database of more than 7 million patients. Scientists found that the Sildenafil is associated with an almost 69% reduced incidence of Alzheimer’s disease. However, further studies are required to test the drug’s efficiency in patients with the disease.
Feixiong Cheng, Ph.D. of Cleveland Clinic’s Genomic Medicine Institute, said, “Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself. Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”
Drug repurposing – using an existing drug for new therapeutic purposes – offers a practical alternative to the costly and time-consuming traditional drug discovery process. Understanding subtypes (endophenotypes) of neurodegenerative diseases such as Alzheimer’s disease may help to reveal common underlying mechanisms. It may also lead to the discovery of actionable targets for drug repurposing.
Until now, no particular treatment for Alzheimer’s disease exists. Plus, many clinical trials for such treatments have been failed in the past decade.
Recent studies highlight the role of the interplay between amyloid and tau in developing Alzheimer’s. In this new study, scientists hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.
Scientists used an extensive gene-mapping network to integrate genetic and other biologic data. Doing so, they wanted to determine which of over 1,600 FDA-approved drugs could be an effective treatment for Alzheimer’s disease. They pinpoint drugs that target both amyloid and tau as having higher scores than drugs that target just one or the other.
Dr. Cheng said, “Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate.”
Scientists used an extensive database of claims data of more than 7 million people in the U.S. to examine the relationship between Sildenafil and Alzheimer’s disease outcomes by comparing sildenafil users to non-users. The analysis included patients using comparator drugs in an active Alzheimer’s clinical trial (losartan or metformin) or was not yet reported as relevant to the disease (diltiazem or glimepiride).
Scientists found that sildenafil users were 69% less likely to develop Alzheimer’s than non-sildenafil users after six years of follow-up. More importantly, the drug had a 55% reduced risk of the disease compared to losartan, 63% compared to metformin, 65% compared to diltiazem, and 64% compared to glimepiride.
Dr. Cheng said, “Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without.”
To further determine the Sildenafil’s effect on Alzheimer’s disease, scientists developed an Alzheimer’s patient-derived brain cell model using stem cells. The model reveals that Sildenafil increased brain cell growth and decreased hyperphosphorylation of tau proteins.
Dr. Cheng said, “Because our findings only establish an association between sildenafil use and reduced incidence of Alzheimer’s disease, we are now planning a mechanistic trial and a phase II randomized clinical trial to test causality and confirm Sildenafil’s clinical benefits for Alzheimer’s patients. We also foresee our approach being applied to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, to accelerate the drug discovery process.”
Journal Reference:
- 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). DOI: 10.1038/s43587-021-00138-z