Monday, 17 January 2022 01:56

Cleveland Clinic research identifies sildenafil as a candidate drug to fight Alzheimer's disease

Written by Evelyn Alas

A new Cleveland Clinic-led study 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 findings published in Nature Aging, the research team, led by Feixiong Cheng, Ph.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 of a database of more than 7 million patients, they determined that sildenafil is associated with a 69% reduction in Alzheimer's incidence, indicating the need for follow-up testing in clinical trials of the drug's efficacy in patients with Alzheimer's disease.

Without the development of effective new treatments, Alzheimer's is projected to impact 13.8 million Americans by 2050, highlighting the need for rapid development of prevention and treatment strategies.

Drug repurposing, which is the use of 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, Ph.D., program director of Translational

Bioinformatics and Drug Development 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 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 accumulation of amyloid beta 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 anti-amyloid or anti-tau small-molecule Alzheimer's treatments, and many clinical trials for these treatments have failed over the past decade.

"Recent studies show that the interaction between amyloid and tau contributes more to Alzheimer's than either of them alone, commented Dr. Cheng. "Because of this, we hypothesized that drugs that target the intersection of the molecular network 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 the more than 1,600 FDA-approved drugs might be an effective treatment for Alzheimer's disease.

They noted that drugs that target both amyloid and tau have higher scores compared with drugs that target only one or the other.

"Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, emerged as the best candidate drug", Dr. Cheng said.

The research team used a large database 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 with non-users. The analysis included to compare patients using drugs that were either in an active Alzheimer's clinical trial (losartan or metformin) or had not yet been reported as relevant to the disease (diltiazem or glimepiride).