A drug for erectile dysfunction could effectively treat a deadly brain disease

Part of the problem with finding a new drug to treat a lethal, currently incurable brain disease is that even when scientists happen upon a promising candidate, they then have to go through a lengthy, at times bureaucratic, clinical trial process to assess the drug’s safety, effects, and long-term capabilities; after all that, there’s a secondary federal approval process — together these can take years. There is another way, however — and a new paper in Nature Aging suggests one group of scientists may have discovered an alternate, faster path to treatment.

What’s new — In a study published Monday in Nature Aging, Feixiong Cheng and his colleagues at The Cleveland Clinic lay out their evidence for an excellent, albeit unexpected, candidate drug that could be repurposed into a medication to treat Alzheimer’s disease: sildenafil.

Sildenafil is the generic form of Viagra, a common erectile dysfunction medication. In the case of this study, the researchers used a cell model to investigate sildefanil’s effects on neurons that mimicked Alzheimer’s disease-affected neurons and combined that with an analysis of medical insurance records to see if there was a correlation in Sildenafil prescriptions and reduced instance of Alzheimer’s disease.

“FDA-approved drugs have well-known safety profiles compared to de novo [new] molecules,” Cheng tells Inverse.

“If we can find an existing FDA-approved drug for [Alzheimer’s disease], we can perform phase II clinical trial [and] skip the preclinical studies and phase I trials, which can significantly reduce cost and time of drug discovery.”

Why it matters — Alzheimer’s disease is the most common type of age-related dementia and ultimately lethal. The Alzheimer’s Association notes “among people age 70, 61 percent of those with Alzheimer's dementia are expected to die before the age of 80 compared with 30 percent of people without Alzheimer's — a rate twice as high.”

Targeted treatments that both reduce the risk of developing the disease, mitigate its symptoms, or slow its progress would transform the lives of millions.

Model-based studies like this one aren’t a substitute for clinical trials, but the results are enough to suggest that sildenafil is a promising drug for Alzheimer’s disease and worthy of further study.

“Based on our study, we think sildenafil will have intervention effects as well beyond prevention as multiple preclinical studies have shown treatment effects of sildenafil in various [Alzheimer’s disease] mouse models,” Cheng says.

Here’s the background — Alzheimer’s disease is characterized by the development of a certain kind of plaque in the brain called amyloid-β plaque that clumps together and disrupts cell function.

A protein called tau is also in play in the development and progression of the disease. In healthy brains, tau binds to and stabilizes microtubules in neurons. When someone has Alzheimer’s disease, chemical changes occur that cause tau to detach from the microtubules and stick to each other, forming tangles. These tangles then interrupt neuronal activity.

A person with a close relative with Alzheimer’s disease is much more likely to develop it than someone without that connection, which is why Cheng and his colleagues decided to look at the “endophenotypes” associated with Alzheimer’s disease.

An endophenotype is a measurable, heritable, biological marker of a disease that can reveal the root cause and mechanisms driving the disease and its progression. In this case, the authors note in the study that both amyloid and tau pathology have commonly shared endophenotypes.

While some Alzheimer’s treatments are aimed either at amyloid-β plaque or tau protein function, these researchers take a third approach: Targetting both problems with one drug.

How they did it — In the study, the researchers used computational techniques to look for existing FDA-approved drugs that acted on several different endophenotypes linked to Alzheimer’s disease. That search gave them 1,600 possible drug candidates, and among the most promising was sildenafil (generic Viagra).

Next, the researchers poured through a dataset of insurance claims and found that people on sildenafil also have a significantly reduced risk of Alzheimer’s disease — 69 percent reduced risk — compared to people not on the drug.

After these analyses, the researcher then performed in-vitro experiments to see if sildenafil affected neurons that were designed to mimic Alzheimer’s disease. They used iPSC neuron models, a kind of brain cell model which was generated using stem cells taken from people with Alzheimer’s disease.

The researchers let those neurons mature in vitro, and once they had, the researchers treated some of those neurons with sildenafil.

The neurons that were treated with sildenafil in vitro had elevated neuronal growth and reduced tau accumulation compared to controls.

“In our iPSC neuron study, we found that sildenafil has neuroprotective effects and reduced hyperphosphorylation of Tau (a hallmark of [Alzheimer’s disease]) in iPSC neurons from patients with [Alzheimer’s disease],” Cheng explains.

What’s next — Cheng and his colleagues are already planning a Phase II clinical trial to further test the potential therapeutic benefits of sildenafil in people with early-stage Alzheimer’s disease. If Phase II and, eventually, Phase III trials are successful, the drug may become available to people with Alzheimer’s faster than would a novel drug — because sildenafil is already FDA-approved for other conditions like erectile dysfunction.

That’s optimistic and hopeful news for the millions of people who have Alzheimer’s or have loved ones suffering from this insidious disease — and may be at risk of developing it themselves.

Abstract: We developed an endophenotype disease module-based methodology for Alzheimer’s disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case–control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio 0.31, 95% confidence interval 0.25–0.39, P < 1.0 × 10–8). Propensity score-stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts tested (diltiazem, glimepiride, losartan and metformin) after adjusting for age, sex, race and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho-tau expression in neuron models derived from induced pluripotent stem cells from patients with AD, supporting mechanistically its potential beneficial effect in AD. The association between sildenafil use and decreased incidence of AD does not establish causality, which will require a randomized controlled trial.