Cleveland Clinic research identifies sildenafil as a candidate drug for Alzheimer’s disease

• Findings published in Nature Aging show a 69% reduction in the likelihood of developing the disease.

January 2021.- A new study led by Cleveland Clinic has identified sildenafil, an FDA-approved therapy for erectile dysfunction (Viagra) and pulmonary hypertension (Revatio), as a promising candidate drug to help prevent and treat Alzheimer’s disease.

According to the findings published in Nature Aging, the research team, led by Feixiong Cheng, Ph.D., of Cleveland Clinic’s Genomic Medicine Institute, used computational methods to screen and validate FDA-approved drugs as potential therapies for Alzheimer’s disease. Through a large-scale analysis of a database of more than 7 million patients, they determined that sildenafil is associated with a 69% reduced incidence of Alzheimer’s disease, indicating the need for follow-up clinical trials testing the drug’s efficacy in patients with the disease.

Without the development of effective new treatments, Alzheimer’s disease will affect 13.8 million Americans by 2050, underscoring 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 drug discovery process.

“This paper is an example of a growing area of research in precision medicine where big data is key to connecting the dots between existing drugs and a complex disease like Alzheimer’s,” said Jean Yuan, M.D., Ph.D., Translational Bioinformatics and Drug Development program director at the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), which funded this research. “This is one of 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.”

Dr. Cheng’s team has found that understanding the subtypes (endophenotypes) of neurodegenerative diseases such as Alzheimer’s can help reveal common underlying mechanisms and lead to the discovery of actionable targets for drug repurposing.

The build-up 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 amount and location of these proteins in the brain can help define endophenotypes. However, there are currently no FDA-approved small-molecule anti-amyloid or anti-tau Alzheimer’s treatments, and many clinical trials for such treatments have failed over the past decade.

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s disease than either by itself,” said Dr. Cheng. “Therefore, we hypothesised that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

Using a large gene mapping network, the researchers integrated genetic and other biological data to determine which of more than 1,600 FDA-approved drugs could be an effective treatment for Alzheimer’s disease. They found that drugs targeting both amyloid and tau scored higher than drugs targeting just one or the other. “Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, emerged as the best drug candidate,” said Dr. Cheng.

The research team used a large database of insurance claims data from more than 7 million people in the United States to examine the relationship between sildenafil and Alzheimer’s disease outcomes by 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 had not yet been reported as relevant to the disease (diltiazem or glimepiride).

They found that sildenafil users were 69% less likely to develop Alzheimer’s disease than non-sildenafil users after 6 years of follow-up. Specifically, sildenafil was associated with a 55% lower risk of the disease compared with losartan, 63% compared with metformin, 65% compared with diltiazem and 64% compared with glimepiride.

“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 them,” added Dr. Cheng.

To further explore sildenafil’s effect on Alzheimer’s disease, the researchers developed a model of brain cells derived from Alzheimer’s patients using stem cells. In the model, they found that sildenafil increased brain cell growth and decreased hyperphosphorylation of tau proteins (a hallmark that leads to neurofibrillary tangles), offering biological insight 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 randomised clinical trial to test causality and confirm sildenafil’s clinical benefits for Alzheimer’s patients,” said Dr. Cheng. “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.”

Jiansong Fang, Ph.D., a former researcher in Dr. Cheng’s lab; Pengyue Zhang, Ph.D., assistant research professor at Indiana University School of Medicine; Yadi Zhou, Ph.D., a data scientist in Dr. Cheng’s lab; and Chien-Wei Chiang, Ph.D., research scientist at The Ohio State University College of Medicine, are co-authors. Dr. Cheng presented the initial findings at the Alzheimer’s Association International Conference 2021. The study was supported by NIA, NIH grants R01AG066707 and R01AG066707-01S1, and the Translational Therapeutics Core of the ClevelandAlzheimer’s Disease Research Center.

About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical centre that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based on the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States.

Find out more about AF comunicacion estrategica and its clients