By Researchers from the Genomic Medicine Institute at the Cleveland Clinic are hoping to use the drug known as sildenafil, sold under the brand name Viagra, as a potential treatment for Alzheimer’s disease. They are testing a multi-prong approach that targets the abnormal clumps of misfolded beta-amyloid proteins in the brain. If their study proves to be a success, Viagra could be in high demand.
Hiding in Plain Sight
There is no cure for Alzheimer’s disease but there are various medications and strategies for reducing the severity of symptoms. It’s thought to be caused by a mix of genetic and environmental factors.
At the outset, researchers looked at the mechanisms that contribute to the disease, including amyloid plaques in the brain, tangled bundles of tau proteins, and the loss of connection between nerve cells in the brain. They published their initial findings in Nature Aging.
Next, they used computer modeling to analyze how some 1,600 prescription medications interact with the brain to see whether these various treatments could unlock new treatments. They eventually narrowed their list to just 66 medications with sildenafil showing the most potential.
The drug is commonly used to treat erectile dysfunction in people with penises as well as high blood pressure in the lungs. It appeared to be the most effective when it came to blocking the stages of Alzheimer’s.
The team then looked at over seven million insurance claims for prescriptions of sildenafil in the U.S. They found that patients who had been prescribed the drug appeared to have a 69% reduced risk of Alzheimer’s over the next six years. Their findings held true even when they accounted for other factors, such as age, ethnic group, gender, and other health conditions.
To confirm their findings, they tested sildenafil’s ability to reduce the harmful effects of Alzheimer’s. The results showed that the drug reduced the signs of the disease in brain cells, including a decrease in tau accumulations.
The study shows that sildenafil may work as a treatment for Alzheimer’s disease in the future. Several studies involving mice and a few pilot studies have resulted in similar findings.
However, the authors of the study say they will need to conduct a clinical trial to make sure the drug can be used as an effective treatment. They said the original study faced limitations and there is more work to be done.
Despite these limitations, the medical community was thrilled with the results.
“Given the urgent need for an effective treatment for Alzheimer’s disease, the observation that Viagra appears to give protection from this form of dementia—is very intriguing,” said Dr. Richard Killick, a lecturer in the Department of Old Age Psychiatry at King’s College London.
Experts point out that developing and testing possible treatments for Alzheimer’s can be cost-prohibitive for some companies. But relying on existing medications could speed up the development process, leading to “life-changing” dementia treatments sooner, said Dr. Susan Kohlhaas, director of research at Alzheimer’s Research U.K.
Lack of Consensus
Others are skeptical of the results outlined in the study.
“The data from insurance claims are not very detailed and did not include information on other important risk factors for Alzheimer’s like risk genes and level of education,” said Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh in Scotland.
“Women are at greater risk of Alzheimer’s than men and as this drug, sildenafil, is most commonly used for erectile dysfunction, there were fewer women taking sildenafil in this study and the effect on women taking the drug was not as strong. Sildenafil is more often prescribed to wealthy people and low socioeconomic status is associated with higher risk of Alzheimer’s,” Spires-Jones added.
The authors were quick to point out that their study was meant to be observational. The results cannot actually determine whether sildenafil can be used to treat Alzheimer’s.
While Spires-Jones called the data from the lab experiments “promising”, she said it was “much less robust” than the large observational study of insurance claims in the paper.
“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” she said.
Dr. Jack Auty, a medical sciences lecturer at the University of Tasmania in Australia, described the results as “fantastic”, saying it is an “excellent example of the future of medical research.”
“It uses sophisticated statistical methods to combine large, publicly available datasets to generate the paper’s hypothesis,” Auty said. “The datasets include RNA sequencing datasets, which essentially tell us which genes are turned off and which genes are turned up to 11 in animal models of Alzheimer’s disease. As well as drug-target databases which tells us which pathways drugs interact with.
“This is exciting stuff. But we need further research. In the field of Alzheimer’s disease research, we have been excited by many drugs over the years, only to have our hopes dashed in clinical trials. I will be following this research group and the research around sildenafil closely,” he added.
Auty also pointed to several gaps and unexplained variables in the authors’ research.
“These are sneaky things we can’t measure that may explain the effect we are seeing,” Auty said. “In this case there are many potential hidden variables. For example, walking slower has been associated with increased risk of a dementia diagnosis. Not because walking faster prevents dementia, it is because walking speed correlates with health.”
“Now replace walking with sex life. Previous research has shown that people with the early signs of Alzheimer’s disease are, on average, less sexually active. So, sildenafil use could be a spurious correlation—also known as a ‘red herring.’ They did try to control for this by looking into patients with pulmonary hypertension, which is sometimes treated with sildenafil. However, this group did not have a statistically significant decreased risk in Alzheimer’s disease.”
However, Robert Howard, a professor of old age psychiatry at University College London, came out against the study.
“The authors… failed to excite me. Association does not imply causation and one only has to pause for a moment to consider the characteristics of older men who consult with their doctor for drug treatment of erectile dysfunction to understand why they might already be different from someone in the pre-symptomatic stages of Alzheimer’s disease,” said Howard.
“Whilst a randomized clinical trial would be the definitive way to investigate whether the drug can prevent or slow dementia, more sophisticated epidemiological studies would be almost as informative. For example, it would be helpful to control better for wealth and educational levels—which are associated with both increased use of sildenafil and reduced risk of Alzheimer’s disease—and to look to see if the apparently protective effects of the drug increase or decrease with longer follow-up.”
It’s too soon to tell if sildenafil can be used to treat Alzheimer’s, but researchers are closing in on a possible breakthrough.
