Sildenafil Emerges as a Candidate Drug for Alzheimer’s Disease

Sildenafil (Viagra®, Revatio®) shows promise as a candidate drug for prevention or treatment of Alzheimer’s disease (AD), according to Cleveland Clinic-led research published in Nature Aging.

The research team, led by Feixiong Cheng, PhD, of Cleveland Clinic’s Genomic Medicine Institute, used computational methodology to screen and validate FDA-approved drugs as potential therapies for AD. Through a large-scale analysis of an insurance claims database covering more than 7 million individuals, they determined that sildenafil users had a 69% reduction in the incidence of AD over six years of follow-up compared with sildenafil nonusers (hazard ratio = 0.31; 95% CI, 0.25-0.39; P < 1.0 × 10–8).

The findings have prompted plans for a phase 2 randomized clinical trial to assess causality and confirm the potential clinical benefits of sildenafil — currently FDA-approved for treatment of erectile dysfunction and pulmonary arterial hypertension — for individuals with or at risk of AD.

A focus on understanding endophenotypes

In previous work, Dr. Cheng’s team has found that understanding subtypes, or endophenotypes, of neurodegenerative diseases such as AD may help reveal common underlying mechanisms and lead to discovery of actionable targets for drug repurposing (i.e., use of an existing drug for new therapeutic purposes).

The buildup of beta amyloid and tau proteins in the brain that lead to amyloid plaques and tau neurofibrillary tangles — two hallmarks of AD-related brain changes — are caused by amyloidosis and tauopathy. The amount and location of these proteins in the brain may help define endophenotypes. However, there are presently no FDA-approved anti-amyloid or anti-tau treatments for AD, as numerous 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 than either is by itself,” says Dr. Cheng. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

Insights from big-data gene mapping

Using a large gene-mapping network, the researchers mapped the interactions between genes/proteins involved in amyloidosis and tauopathy to build connected sub-networks linked to these endophenotypes that may be synergistic. They then measured proximity of the sub-networks to drug targets of more than 1,600 FDA-approved drugs, where closer proximity indicates a greater likelihood that a drug could be an effective AD treatment.

“We found that drugs targeting both amyloid and tau had significantly closer network proximity with the modules compared with those targeting just one or the other,” Dr. Cheng notes. “Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate.”

Sildenafil stands out from comparator drugs

The researchers drew on medical and pharmacy claims for 7.23 million individuals in the MarketScan Medicare Claims database from 2012 to 2017 to examine the relationship between sildenafil and AD outcomes by comparing sildenafil users to nonusers. They also analyzed data for patients receiving widely used comparator drugs that were in an active AD clinical trial (losartan and metformin) as well as others not yet reported as relevant to the disease (diltiazem and glimepiride).

In addition to finding that sildenafil users were 69% less likely to develop AD than nonusers over six years of follow-up, the analysis showed that sildenafil use reduced the risk of AD development as follows (after adjusting for age, sex, race and comorbidities):

• By 55% relative to losartan
• By 63% relative to metformin
• By 65% relative to diltiazem
• By 64% relative to glimepiride

“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 Alzheimer’s — as well as in those without these conditions,” Dr. Cheng notes.

Mechanistic insights — and plans for further study

To further explore sildenafil’s effect on AD, the researchers developed an AD patient-derived brain cell model 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 AD incidence, we are now planning a mechanistic trial and a phase 2 randomized clinical trial to test causality and confirm sildenafil’s clinical benefits for AD patients,” says 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.”

Additional perspectives

“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,” says Jean Yuan, MD, PhD, who directs the Translational Bioinformatics and Drug Development Program at the National Institute on Aging, which funded this research. “This is one of many efforts we are supporting to find existing drugs or available safe compounds for other conditions that would be good candidates for Alzheimer’s disease clinical trials.”

“This an impressive investigation that has discovered a novel association between sildenafil and a reduced risk of AD diagnosis after analyzing data from over 7 million individual medical records,” adds Jagan Pillai, MD, PhD, a staff neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health. “As other co-existing clinical factors could also contribute to the association, additional clinical trials in patients with AD are needed to understand whether this medication is clinically helpful.”