Viagra Prescription Associated With a 69% Reduction in Alzheimer’s Risk

 A study looking at the potential of repurposing licensed drugs for the treatment of Alzheimer’s disease has identified the erectile dysfunction drug sildenafil, brand name Viagra, as a candidate for future analysis.

The search for drugs that can treat the symptoms of Alzheimer’s disease effectively has become a long and costly project. The last major advance in our understanding of this condition arguably happened prior to the 21^st century, with the identification of the role of the proteins tau and amyloid in the spread of Alzheimer’s through the brain.

Since then, numerous trials have been undertaken to test drugs based on the amyloid and tau hypotheses in patients with Alzheimer’s disease. From the early 2000s until last year, all had failed. While the qualified approval of the anti-amyloid monoclonal antibody aducanumab provides some hope that research into Alzheimer’s is at least aiming in the right direction, the immense cost and serial failure of prior trials have led to companies and academics examining alternative routes to drug development. One of these options is based on finding already-approved compounds that may be repurposed for Alzheimer’s disease.

Viagra finding perks up Alzheimer’s drug search

A new study, armed with an innovative, computational drug development approach, has identified the erectile dysfunction drug sildenafil, known to millions of men around the world as Viagra, as a compound linked to a lower risk of Alzheimer’s disease. Viagra, approved in the US in 1998 and patented by Pfizer, is an artificial compound that was originally designed to treat cardiovascular disease. The drug did little to treat angina, but its unexpected and enervating side effects made it a worldwide success.

The new research was published in Nature Aging by senior author and Case Western Reserve University professor Feixiong Cheng and colleagues. The team built a dataset of genes, RNA molecules and proteins that have been linked to Alzheimer’s disease in previous studies. This was mapped onto a vast model of the human protein interactome – which records how protein molecules relate to each other at a molecular level during biochemical activity. The model captured over 350,000 interactions spread over 17,706 different proteins.

Cheng’s team then used this data as a canvas on which to sketch out the drug-target interactions of more than 1,600 drugs approved by the US Food and Drug Administration (FDA). Drugs were scored, with the top performing compounds having the strongest relationship to Alzheimer’s disease-linked molecules.

In total, the groups had created 13 different sub-datasets, which they called endophenotype modules, based on their data. They looked at which of the top 100 scoring drugs interacted with more than four of the modules. They whittled down the list to 21 drugs that had also been previously investigated in Alzheimer’s disease. These finalists had a huge range of approved uses: the anesthetic lidocaine featured, as did the anti-ALS drug riluzole and the muscle relaxant dantrolene. After ruling out compounds already under investigation for Alzheimer’s disease and those with insufficient patient data, Viagra was the only top performer left standing.

Insurance analysis

To make sure that their computational approach had some basis in real-life data, the team analyzed insurance claims from seven million Viagra users in the US. Prescription of Viagra was associated with a 69% reduction in the risk of Alzheimer’s diagnosis in the following six years. To examine what molecular mechanisms might explain this, the team dosed neurons in a dish derived from the stem cells of Alzheimer’s disease patients, showing that it increased the growth of neural connections and reduced the accumulation of tau protein.

The promise of these findings is a qualified one. The computational approach taken was not capable of establishing causality, meaning there was no way to conclusively say that taking Viagra reduced risk of Alzheimer’s disease in the insurance claim cohort.

Another significant factor is Viagra’s somewhat specialized indication. Only 2% of people claiming for the drug were women, who make up the majority of the Alzheimer’s disease patient population. Dr. Susan Kohlhaas, director of research at Alzheimer’s Research UK, who was not involved in the study said in a press release: “While the researchers did look at the effect of sildenafil on females, there isn’t enough information to be able to accurately draw conclusions about its effect in females.

Kohlhaas also addressed the need for future experiments to back up the paper. “The researchers have conducted lab-based experiments to give an indication as to why the drug may impact diseases like Alzheimer’s, but these early-stage experiments would need follow-up in more thorough tests,” she said.

While Viagra’s reputation might drive the study into the headlines, it is the computational repurposing approach the researchers adopted that may yet prove most significant to drug discovery – providing a cheaper and faster route to potential treatments. “Developing drugs for diseases like Alzheimer’s, which attack the brain, is a costly process and can take many years. Being able to repurpose a drug already licensed for other health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” said Kohlhaas.

Reference:  Fang, J, Zhang, P, Zhou, Y et al. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nature Aging. 2021. doi: 10.1038/s43587-021-00138-z