Sildenafil, an FDA-approved therapy for erectile dysfunction (Viagra) and pulmonary hypertension (Revatio), may be a promising drug candidate to help prevent and treat Alzheimer’s disease, a new study reveals. Cleveland Clinic Research.
According to the findings of this research published in Nature Aging, The research team, led by Feixiong ChengPh.D., of the Cleveland Clinic Institute for Genomic Medicine, used computational methodology to screen and validate FDA-approved drugs as potential therapies for Alzheimer’s disease.
Through a large scale analysis from a database of more than 7 million patients, determined that the Sildenafil is associated with a 69% reduced incidence of Alzheimer’s diseasepointing to the need for follow-up evidence from clinical trials of the drug’s efficacy in patients with the disease.
The findings of the team led by Feixiong Cheng show that Sildenafil reduces the probability of developing Alzheimer’s by 69%
Dr. Cheng’s team has found that understanding subtypes (endophenotypes) of neurodegenerative diseases such as Alzheimer’s disease may help reveal common underlying mechanisms and lead to the discovery of actionable targets for drug reuse.
The accumulation of beta amyloid and tau proteins in the brain leads to amyloid plaques and tau neurofibrillary tangles, two hallmarks of Alzheimer’s-related brain changes. The quantity and location of these proteins in the brain can help define endophenotypes. However, there are currently no FDA-approved anti-amyloid or anti-tau small molecule Alzheimer’s treatments, and many clinical trials for such treatments have failed in the past decade.
As Dr. Cheng points out, “Recent studies show that the interaction between amyloid and tau is a greater contributor to Alzheimer’s disease than either alone.” “Therefore, we hypothesize that drugs that target the intersection of the molecular network of amyloid and tau endophenotypes should have the greatest potential for success«.
Sildenafil significantly improves cognition and memory in preclinical models
Using a large genetic mapping network, researchers at integrated genetic data and other biological data to determine which of the more than 1,600 FDA-approved drugs might be an effective treatment for Alzheimer’s disease.
They found that drugs that target both amyloid and tau have higher scores compared to drugs that target only one or the other. «Sildenafilwhich has been shown to significantly improves cognition and memory in preclinical models, it appeared as the best drug candidate”said Dr. Cheng.
The research team used a large database of claims data from more than 7 million people in the United States to examine the relationship between sildenafil and Alzheimer’s disease outcomes comparing sildenafil users with non-users. The analysis included patients using comparator drugs that were in an active Alzheimer’s clinical trial (losartan or metformin) or not yet reported as relevant to the disease (diltiazem or glimepiride).
The researchers found that the Sildenafil users were 69% less likely to develop Alzheimer’s disease that users do not sildenafil after 6 years of follow-up. Specifically, the sildenafil had a 55% lower risk of disease compared to losartan63% compared to metformin, 65% compared to diltiazem, and 64% compared to glimepiride.
“In particular, we found that the use of sildenafil reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension and type 2 diabetesall of which are comorbidities significantly associated with the risk of the disease, as well as in those without it»stresses Dr. Cheng.
To further explore the effect of sildenafil on Alzheimer’s disease, the researchers developed a model of brain cells derived from Alzheimer’s patients using mother cells. In the model, they found that the sildenafil increased brain cell growth and decreased hyperphosphorylation of tau proteins (a hallmark leading to neurofibrillary tangles), offering biological insights into how sildenafil may influence disease-related brain changes.
“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 prove causality and confirm clinical benefits of sildenafil for Alzheimer’s patients«. “We also envision our approach being applied to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosisto speed up the drug discovery process»concludes Dr. Cheng.
He ‘big data‘ is key to connecting existing drugs and Alzheimer’s
Without the development of new effective treatments, the need for rapid development of prevention and treatment strategies. Drug repurposing (using an existing drug for new therapeutic purposes) offers a practical alternative to the costly and time-consuming traditional process of drug discovery.
“This paper is an example of a growing area of precision medicine research where the ‘big data‘ is key to connecting the dots between existing drugs and a complex disease like Alzheimer’s.”it states jean yuan, MD, Ph.D., director of the Translational Bioinformatics and Drug Development program at the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). who have funded this research.
“This is one of the many efforts we are supporting to find existing drugs or safe compounds available for other conditions that would be good candidates for Alzheimer’s disease clinical trials.”says this expert.