Scientists have reacted to the "extremely exciting" findings of research that identified the medication sildenafil, marketed under the brand name Viagra, as a possible therapy for Alzheimer's disease, the most prevalent cause of dementia.
Researchers in the study, coordinated by a team from the Cleveland Clinic's Genomic Medicine Institute, came to this result after taking a multi-pronged strategy.
First, the researchers discovered gene and protein clusters linked to the pathways involved in Alzheimer's disease development.
A complicated combination of genetic and environmental variables is assumed to be the origin of the disease, which steadily degrades memory and cognitive skills.
At the biochemical level, aberrant aggregates of misfolded beta-amyloid proteins in the brain, known as amyloid plaques, and tangled bundles of another protein known as tau are among the key characteristics of Alzheimer's. Another hallmark is the loss of nerve cell connections in the brain.
The authors of the study, which was published in the journal Nature Aging, used computer modeling to see how closely more than 1,600 commonly prescribed drugs interact with the clusters of genes and proteins in order to predict which of the substances could potentially provide new treatments.
The list was pared down to 66 medications, with sildenafil—a drug routinely used to treat erectile dysfunction as well as high blood pressure in the lungs—appearing to be the most promising choice for inhibiting the destructive processes that occur in Alzheimer's disease.
After that, the authors looked at almost seven million insurance claims for sildenafil prescriptions in the US. According to this study, claimants who were administered the medicine had a 69 percent lower chance of Alzheimer's disease over the next six years.
Even after accounting for other characteristics that increase Alzheimer's risk, such as sex, ethnicity, and specific medical problems, this conclusion remained statistically significant.
Finally, the researchers conducted laboratory studies to see how sildenafil interacted with nerve cells from Alzheimer's sufferers. They discovered that the medication decreased specific symptoms of the illness in the cells, such as tau accumulations.
The study's findings support the hypothesis that medicine may be used to treat the condition. Previous investigations in rodents and a small number of human pilot trials have also suggested that the medication might be useful for this purpose.
However, the authors of the Nature research emphasize that its efficacy can only be shown once clinical studies that appropriately analyze such treatment have been undertaken.
They point out that the study has various flaws and does not prove a causal relationship between sildenafil usage and a decreased risk of Alzheimer's disease.
Despite this, some experts have praised the new results, praising them as a significant addition to the field's academic literature.
"Given the urgent need for an effective therapy for Alzheimer's disease, the discovery from Fang et al—that Viagra appears to confer protection from this kind of dementia—is quite fascinating," said Dr. Richard Killick, a lecturer in the Department of Old Age Psychiatry at King's College London.
Because developing drugs for diseases like Alzheimer's is expensive and takes years, repurposing a drug that is already approved for another medical condition could speed up the development of "life-changing" dementia treatments, according to Dr. Susan Kohlhaas, director of research at Alzheimer's Research U.K.
However, other academics, including the authors, have pointed out that there are numerous key constraints to consider.
"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," Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh in Scotland, said in a statement.
Furthermore, "Women have a higher risk of Alzheimer's disease than males, and because this medicine, sildenafil, is most widely used for erectile dysfunction, there were fewer women in our trial, therefore the effect on women was not as severe. Sildenafil is more commonly supplied to the rich, and poor socioeconomic level is linked to an increased risk of Alzheimer's disease."
As the authors point out, this sort of information is insufficient to evaluate if the medicine truly prevents or cures the condition.
While the evidence from the lab tests was "promising," it was "far less solid" than the massive observational research of insurance claims included in the report, according to Spires-Jones.
"While these findings are intriguing from a scientific standpoint, I would not recommend starting sildenafil as a preventative for Alzheimer's disease based on this study," she added.
The work was characterized as "wonderful" by Dr. Jack Auty, a medical sciences lecturer at the University of Tasmania in Australia, who called it a "great illustration of the future of medical research."
"It generates the paper's hypothesis using advanced statistical approaches that integrate massive, publicly available information," he stated. "Among the databases are RNA sequencing datasets, which effectively tell us which genes in animal models of Alzheimer's disease are shut off and which ones are turned up to 11." Drug-target databases, which inform us which pathways medicines interact with, are also available.
"This is a lot of fun. However, more study is required. Many medications in the field of Alzheimer's disease research have piqued our interest throughout the years, only to be crushed in clinical trials. I'll be keeping a careful eye on this study group and the sildenafil research."
Auty also pointed out that the study had a number of limitations, many of which are acknowledged by the authors. Hidden variables, for example, are one of the constraints in insurance data.
Auty explained, "These are subtle things we can't measure that may explain the effect we're witnessing." "There are a lot of hidden factors in this situation." Slower walking, for example, has been linked to an increased chance of dementia diagnosis. Walking faster does not prevent dementia; rather, walking speed is linked to health.
"Substitute sex life for walking. A previous study has found that those who are showing early indications of Alzheimer's disease are less sexually active on average. As a result, sildenafil usage might be a red herring,' or a misleading link. Patients with pulmonary hypertension, which is sometimes treated with sildenafil, were studied to see if this was a factor. However, there was no statistically significant reduction in the risk of Alzheimer's disease in this group."
Finally, the researchers employed medication concentrations in the lab nerve cell trials that were 100 times higher than those attained when taking a tablet, according to Auty.
The findings of the current study, according to Dr. Mark Dallas, an associate professor of cellular neuroscience at the University of Reading in England, imply sildenafil is a "potential weapon" in the armory against the condition, albeit it does not prove it is the "silver bullet."
"Sildenafil has already been tested on a limited group of patients, and it's not the first time it's been discovered as a potential treatment," he said. "However, this study adds to the need for more clinical studies to determine its genuine benefit for Alzheimer's."
Robert Howard, a professor of old age psychiatry at University College London, was among those who were less enthusiastic about the study.
"I was underwhelmed by the authors. To understand why older men who consult with their doctor for drug treatment of erectile dysfunction might already be different from someone in the pre-symptomatic stages of Alzheimer's disease, consider the characteristics of older men who consult with their doctor for drug treatment of erectile dysfunction "he stated
"While a randomized clinical trial would be the most conclusive approach to see if the medicine may prevent or reduce dementia, more advanced epidemiological research would be almost as useful. For example, it would be beneficial to better control for affluence and educational levels—both of which are linked to increasing sildenafil usage and a lower risk of Alzheimer's disease—and to observe if the drug's ostensibly protective benefits improve or diminish with longer follow-up."