December 6, 2021

expert reaction to study identifying sildenafil (Viagra) as a candidate drug for Alzheimer’s disease

A study published in Nature Aging identifies sildenafil as a candidate drug for Alzheimer’s disease.

Prof Tara Spires-Jones, Deputy Director of the Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This study by Dr Cheng and colleagues used computer modelling and data from insurance claims from over 7 million people to look for potential drugs that may prevent Alzheimer’s disease.  This study looks at data from a very large number of people, but there are several important limitations 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.   Women are at greater risk of Alzheimer’s than men and as this drug, sildenafil (also known as Viagra), 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.  

“As the authors point out, this type of data cannot determine whether this drug, actually prevents Alzheimer’s disease.  There are other possible explanations for these findings; for example, we know that brain changes start decades before dementia symptoms and it is possible that these early Alzheimer’s changes reduce sex drive (thus people wouldn’t ask for a prescription for erectile dysfunction).

“Alongside the data from people taking this drug having lower chances of developing Alzheimer’s, the scientists present data showing that sildenafil lowered the amount of an Alzheimer’s-related protein tau in brain cells programmed from stem cells from one person who had Alzheimer’s. While this is promising, these cell data are much less robust than the large observational study of insurance claims.  More work will be needed to know whether this drug can indeed lower risk for Alzheimer’s disease.

“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.”

Prof Robert Howard, Professor of Old Age Psychiatry, UCL Division of Psychiatry, said:

“The authors try to build a case for sildenafil (Viagra) as a potential treatment for Alzheimer’s disease, mostly by showing an association between prescription of the drug and a reduced risk of being diagnosed with dementia over 6 years. They 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. 

“Whilst a randomised 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. An increased in dementia protection with longer follow-up would argue against the confounding effects of imbalance of baseline pre-symptomatic cases in the non-treatment group which most probably explain these latest results.”

Dr Jack Auty, lecturer in the Medical Sciences at the University of Tasmania, said:

“This is a fantastic paper. 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 – leaving biased human ‘wetware’ out of it. The datasets include RNA sequencing datasets, which essentially tell us which genes are turn 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. By combining these and other datasets, the statistics are able to generate a list of drugs which may help by blocking the damaging processes which occur in Alzheimer’s disease. The top of the list was sildenafil, more commonly known as Viagra.

“They then looked in insurance databases and established that people taking sildenafil had a lower risk of developing Alzheimer’s disease. They also performed cell experiments (essentially neurons in a flask) to establish that sildenafil was having the predicted effect on the biological process identified in the statistics. Very fascinating research.

“All research has caveats and many of these caveats were acknowledged by the authors. The first one is in data science we have a phrase “garbage in, garbage out”. What we mean by this is no matter how fantastic your analysis is, if the data going into the analysis is not great, then the results of the analysis will also be not great. In this case a lot of data going into the original analysis was generated from animal models of Alzheimer’s disease. And unfortunately these models have severe limitations. This is evidenced by the fact that scientists have cured Alzheimer’s disease in mice thousands of times, and yet despite billions of dollars of clinical trials, we are yet to have a good disease modifying drug in the clinic (in my opinion). To overcome this limitation, the paper used data from many different mouse models of Alzheimer’s disease which helps to mitigate the shortcomings of any one animal model; though I am unsure why they did not also use the RNA sequencing data from human brains that is available. 

“A limitation in the insurance data analysis is a thing we call hidden variables. These are sneaky things we can’t measure that may explain the effect we are seeing. 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 – aka 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. 
Sexual Function in Normal Elders, MCI and Patients with Mild Dementia | SpringerLink

“Lastly, the cell culture experiments used concentrations of the drug around 100 times that achieved by taking the pill. 

“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.”

Dr Ivan Koychev, Senior Clinical Researcher at the University of Oxford, said:

“This is a methodologically complex study in which the authors identified clusters of genes and proteins that associate with the mechanisms involved in Alzheimer’s disease. They then examined if 1608 commonly prescribed drugs are known to interact with the AD gene/protein clusters. Sildenafil, a medication used to treat erectile dysfunction, was found to be linked most closely to AD. They then looked at whether people prescribed sildenafil and found that it associates with a significant reduction in risk of AD when compared to blood pressure or diabetes medications. The authors went on to test how sildenafil interacts with nerve cells derived from Alzheimer’s disease patients and found that it reduced the level of Alzheimer’s pathology there. 

“Overall, this is a very comprehensive piece of research that has provided an example of how complex analytical methods can be used to identify unexpected useful effects of medications that are currently in use. It is an exciting development for Alzheimer’s disease research in particular as it points to a specific drug (sildenafil) which may offer a new approach to treating the condition. It also underscores the value of exploring if available drugs may be useful for changing the course of Alzheimer’s disease. This ‘repurposing’ approach can reduce the drug discovery period by years and reduce the risk of failure as we already know how safe these drugs are in humans.”

Dr Mark Dallas, Associate Professor in Cellular Neuroscience at the University of Reading, said:

“The study has harnessed computer modelling to work out whether currently approved medicines might be able to make a difference for people with Alzheimer’s Disease. Among the 66 drugs already used for other treatments, sildenafil is again identified as a possible weapon in the armoury and deserving of further research although the study does not prove that it is the silver bullet.”

“Sildenafil has already been trialled with a small number of people and it’s not the first time it’s been identified as a potential treatment, but this study certainly adds to the calls for further clinical trials to find out its true value for Alzheimer’s.”

Dr Catherine Hall, Senior Lecturer in Psychology at the University of Sussex who studies how the regulation of the brain’s energy supply (neurovascular coupling) varies during different brain states, across different brain regions and at the onset of conditions such as Alzheimer’s disease and obesity, said:

“A challenge in finding a successful treatment for Alzheimer’s disease is that symptoms only appear after significant neuronal death has occurred – and this cannot then be reversed. A real strength of this work is the ability to record the effects of drugs given for other reasons than for Alzheimer’s disease, and that were therefore able to benefit patients before the development of the disease.  

“The way the study identified sildenafil as an interesting target for further study is clever, but given the list of drugs that emerged from this network analysis was then screened for existing data showing a potential link to Alzheimer’s disease, the method is somewhat circular. It is not clear to me what the advantage of the network analysis is over simply screening any drug that has been shown to have a benefit in small trials or preclinical studies. It might be better to simply perform the analysis of Alzheimer’s Disease risk across more treatments.  

“This research used existing data to construct a network to describe how thousands of proteins interact with proteins associated with Alzheimer’s Disease, and then to find drugs that interact with the most closely associated proteins. From the candidate drugs identified using this data mining of network interactions, the authors selected sildenafil (Viagra) to study further, and then compared data from medical insurance records to understand whether taking sildenafil affected the chance of going on to develop Alzheimer’s disease. They found that sildenafil reduced the chances of developing Alzheimer’s disease, compared to controls, or patients on other drugs. They then suggest that this protective effect occurs by preventing activation of two proteins that affect hyperphosphorylation of tau, and therefore formation of tangles.  

“The authors propose that sildenafil acts on microglia to reduce the activation of proteins that promote tau hyperphosphorylation. This is possible, but there are lots of other ways in which sildenafil could also be having its effects that are perhaps more likely. A reduction in brain blood flow is one of the first things that goes wrong in the development of Alzheimer’s disease – well before symptoms occur.  Sildenafil (commonly known as Viagra) is usually thought of as a cardiovascular drug, and could be having its protective effects by promoting brain blood flow and therefore stopping Alzheimer’s disease from developing. 

“This is not the first time sildenafil has been suggested to be beneficial against Alzheimer’s disease but this study suggests it may be effective early, and is more effective than other drugs that treat cardiovascular problems. 

“However, this could be in part because people who take sildenafil have less serious cardiovascular damage than those who are taking the other drugs to combat hypertension or diabetes. If cardiovascular damage is a key causal factor in developing Alzheimer’s disease, then these people might anyway be at an advantage compared to people who have to take drugs for hypertension, cardiovascular disease or diabetes. The study tried to control for this, but it is not clear if severity of the different conditions controlled for could be taken into account (those with more severe hypertension are presumably more likely to be taking anti-hypertensive medication such as losartan).

“On balance though, because sildenafil reduced Alzheimer’s risk compared to people who had no cardiovascular conditions, it does seem that the drug is doing something, rather than just artefactually selecting a healthier population than other drugs. 

“Sildenafil treatment is an exciting prospect for prevention of Alzheimer’s, but it is not clear how to best move on from this research.  A clinical trial for sildenafil might be a good idea, but sildenafil is very likely to be less effective if given after symptoms have developed. Is it feasible to treat everyone with sildenafil for years before they are likely to develop Alzheimer’s disease, or would this cause more problems than it solves? It might it be better to study the pathway by which these beneficial effects of sildenafil are being mediated and then encourage lifestyle factors (e.g. exercise) that can be shown to reduce risk in the same way.” 

Dr Richard Killick, Lecturer in the Department of Old Age Psychiatry, King’s College London, said:

“Given the urgent need for an effective treatment for Alzheimer’s disease, the observation from Fang et all – that Viagra appears to give protection from this form of dementia – is very intriguing. This is especially encouraging for a number of us at King’s who are looking to repurpose existing drugs for the treatment of several forms of dementia. We are currently commencing a clinical trial to test the drug fasudil in people with a diagnosis of AD. Fascinatingly, Fasudil and Viagra are chemically very similar molecules and although Viagra is an inhibitor of an enzyme named PDE5 it is also able to inhibit the enzyme, ROCK, the primary target of Fasudil. A considerable number of earlier reports have shown that Viagra is protective in animal models of AD. All of this bodes well that either Fasudil or Viagra, or indeed both, could prove to be truly effective treatments for AD.”

Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, said:

“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.

“While sildenafil is most well-known as a treatment for erectile dysfunction, it’s also used to treat high blood pressure in the lungs. In this study, researchers also found that its use is linked with fewer cases of Alzheimer’s disease in American adults. Due to the conditions Viagra (sildenafil) is predominantly prescribed for, most of the recipients of the drug were male. 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, which account for the majority of Alzheimer’s cases worldwide.

“The researchers have conducted lab-based experiments to give an indication as to why the drug may have impact diseases like Alzheimer’s, but these early-stage experiments would need follow-up in more thorough tests.

“Importantly this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease. The only way to test this would be in a large-scale clinical trial measuring sildenafil effect against the usual standard of care.

“It’s important that all avenues for potential drugs are investigated thoroughly and the only way to do this is to keep up momentum in dementia research through continued investment.

“If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”

‘Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease’ by Jiansong Fang et al. was published in Nature Aging at 4pm UK TIME on Monday 6 December.

DOI: https://doi.org/10.1038/s43587-021-00138-z

Declared interests

Dr Mark Dallas: “has nothing to declare.”

Prof Robert Howard: “No relevant conflicts.”

Prof Tara Spires-Jones: “I have no conflicts with this study.”

None others received.