Research News

New Cleveland Clinic-led research demonstrates sildenafil can help protect our brain cells from Alzheimer's disease in preclinical work. Sildenafil is the main component of drugs used to treat pulmonary arterial hypertension (Revatio) and erectile dysfunction (Viagra). 

The study details observations in brain cells in Alzheimer's patients that support earlier computational studies which initially identified the drug's potential as a candidate to treat the devastating neurodegenerative disease. Both studies were led by Feixiong Cheng, PhD, the inaugural Director of the new Cleveland Clinic Genome Center.

Dr. Cheng and his team specialize in systems biology and multi-omics research. They initially integrated data sets from gene expression studies, protein-based studies, anonymized patient data and anonymized insurance records to identify existing medications with potential to also treat Alzheimer's. They published their first set of findings in 2021. 

To make the leap to clinical trials, Dr. Cheng and his team of researchers and clinicians needed experimental proof that sildenafil specifically targets Alzheimer's disease related genes and processes. Now, three years later, they have published that proof in the Journal of Alzheimer's disease.  

"Systems biology and multi-omics research are powerful because the approaches combine so many different types of data, but that's just one part of the greater research journey," explains Dr. Cheng. "To justify using something like Viagra in an Alzheimer's disease clinical trial, we needed to get evidence that what we saw on the screen translated to real life." 

To start, researchers further analyzed millions of anonymized insurance claims from two independent patient databases, which revealed a 30% - 54% reduced prevalence in Alzheimer's disease diagnoses among patients who took sildenafil compared to those who did not, after adjusting for possible confounding factors. The data was compelling evidence, but they still needed to directly observe the drug's effects for themselves.

To do this, Dr. Cheng worked closely with clinicians including Jeffrey Cummings, MD, ScD, and Andrew A. Pieper, MD, PhD. Dr. Cummings is the founding director of the Cleveland Clinic Luo Ruvo Center for Brain Health in Las Vegas. Dr. Pieper runs an outpatient psychiatry clinic at the Louis Stokes Cleveland VA Medical Center and a neurobiology laboratory at Case Western Reserve University and University Hospitals. 

Dish experiments used neurons derived from four different patients, two of whom had an inherited form of Alzheimer's and two of whom had developed the condition spontaneously. Neurons treated with sildenafil had lower levels of phosphorylated tau proteins. Buildup of phosphorylated tau proteins is a key feature of Alzheimer's disease. They also found that neurons treated with sildenafil expressed genes related to neuron generation, neuroplasticity, neural function, neural inflammation and other processes known to protect against the neural degeneration associated with Alzheimer's disease.

While further study is needed to make sure these changes translate into humans and cause Alzheimer's symptoms, the results are promising for repurposing sildenafil, already approved by the FDA for other uses.

Alzheimer's disease currently affects over 6 million Americans, and one in three seniors dies with Alzheimer's or another dementia. If the current lack of treatments, cures and preventative measures continues, this number is expected to triple by 2050. Dr. Cheng's findings demonstrate the feasibility of using computer models to identify potential new drug candidates in a fast, reliable way, representing a significant step forward in Alzheimer's drug discovery.

About this study 

Dhruv Gohel, PhD, and Amit Gupta, PhD, postdoctoral research associates in the Cheng Lab, are the co-first authors of this study, which was supported by the National Institute on Aging under the National Institutes of Health (NIH).