How far is Viagra from being able to treat Alzheimer's disease?

Sildenafil (Viagra) is the most well-known drug for treating male diseases. It was born out of an accident during a trial to treat heart disease. As its mechanism was discovered, scientists discovered other indications for it, such as pulmonary hypertension. Recently, several studies have shown that sildenafil can reduce the risk of Alzheimer's disease. Can it really prevent and treat this disease that affects human cognitive function? To find out whether it can succeed, what other experiments do we need to conduct?

Written by | Wangwang

Figure 1 Sildenafil (Viagra®) Image source: Internet

Sildenafil (Viagra®), you must have heard of its other more well-known name: Viagra. It is a best-selling drug developed by Pfizer for the treatment of male erectile dysfunction (ED). In addition to treating ED, many recent studies have shown that sildenafil is associated with a reduced risk of Alzheimer's disease. This article will introduce you to the legendary development history of sildenafil, as well as the current research progress - how far is sildenafil from treating Alzheimer's disease?

Treatment of ED: Losing in one place but gaining in another

The development of sildenafil for the treatment of ED originated from an accident. As a phosphodiesterase type 5 inhibitor (PDE5-I), sildenafil can inhibit PDE5 from breaking down cyclic guanosine monophosphate (cGMP), causing blood vessels to dilate and thus lowering blood pressure. Therefore, at the beginning of its development, researchers tried to use it to treat cardiovascular diseases such as angina pectoris and hypertension [1].

Figure 2 Mechanism of action of sildenafil[2]

In April 1991, the early clinical trials failed due to unsatisfactory treatment effects on cardiovascular disease. During the clinical research, researchers unexpectedly discovered the side effects of sildenafil: some male volunteers who took relatively high oral doses experienced increased frequency and prolonged erections. Nurses also often observed male patients covering their abdomens to hide their embarrassment. However, after the clinical trial failed, the subjects refused to return the remaining drugs, which the researchers found strange. Upon investigation, they found that sildenafil had improved their sex lives [1].

This discovery sparked the interest of scientists, who began to study the potential of sildenafil in treating erectile dysfunction. After extensive clinical trials and research, in 1998, the U.S. Food and Drug Administration (FDA) approved sildenafil as a drug for the treatment of male erectile dysfunction [3]. This approval opened up a new treatment method and brought good news to men with ED.

The mechanism of action of sildenafil in treating ED was also elucidated. Consistent with the previous conclusions, sildenafil can highly selectively inhibit the activity of PDE5 in the human body. PDE5 is expressed at a very high level in the corpus cavernosum of the penis, but at a lower level in other tissues and organs of the human body. Therefore, it is not very effective in treating cardiovascular diseases, but is suitable for the treatment of ED[4]. After taking sildenafil, the smooth muscle of the corpus cavernosum vessels of the male penis relaxes under the action of the drug, blood flow increases, the corpus cavernosum becomes engorged, and the penis becomes erect, thus achieving a therapeutic effect[2].

After being approved by the FDA and successfully marketed in 1998, sildenafil’s sales in the US market reached $400 million in the first quarter, with more than 300,000 prescriptions written in just one week in May 1998. Pfizer also contributed greatly to this, sending a large number of sales representatives to instruct doctors on how to bring up the then-sensitive topic of impotence and distributing pill samples to treat this disease that has plagued men since ancient times. In the following years, sildenafil’s influence continued to expand, bringing about a revolution in sexual medicine around the world, and bringing Pfizer more than $1 billion in revenue each year worldwide[1].

Viagra®'s patents outside the United States expired in 2012, and in the United States in 2020. After the patent protection period, generic drugs for ED have set off a new wave of market. In China, sildenafil still leads the sales list of chemical drugs every year. In 2021, the total sales of sildenafil in my country will be at least 4 billion yuan. It is worth mentioning that among the top 20 terminal chemical drugs in China's online pharmacies in 2021, sildenafil citrate tablets (Viagra) ranked first with a high growth rate of 61.04% [5].

The launch and popularity of sildenafil marked a new era of medical treatment for sexual medicine. Its significance also opened the door for men to discuss the frustrations they once felt ashamed to talk about, which may be signs of other more serious health problems (including heart disease).

Flowers from old trees: A new use for preventing Alzheimer's disease

In recent years, new uses for old drugs have become common. “New uses for old drugs” refers to the study of drugs that are already on the market or undergoing clinical trials, discovering new indications for them and using them to treat diseases[6]. Given the high R&D costs, long R&D cycles, and high R&D risks of new drugs, developing new uses for old drugs that have been tested can undoubtedly greatly speed up the R&D process.

There are many well-known cases. For example, aspirin, a century-old antipyretic and analgesic drug, has recently been found to have a very good effect in the prevention and treatment of cardiovascular disease[7]. Since its introduction in 1957, metformin, an oral hypoglycemic drug that has been widely used, has also been found to have unique advantages in cardiovascular and cerebrovascular protection. Recent studies have also shown that metformin treatment is associated with a reduced risk of lung cancer, prostate cancer, colorectal cancer, breast cancer and other cancers[8].

The most well-known use of sildenafil, the protagonist of this article, is the treatment of ED. After its successful launch, research on its other indications has not stopped. Pulmonary hypertension is one of them. As a fatal cardiovascular disease, patients will suffer from heart failure and eventually die in severe cases. Subsequent studies have found that sildenafil has a good therapeutic effect on pulmonary hypertension. After years of clinical trials, the FDA approved sildenafil as a drug for the treatment of pulmonary hypertension in 2005, with the trade name "Revatio". The launch of Revatio once changed the high price pattern of drugs for the treatment of pulmonary hypertension and reduced the financial burden on patients.

Nowadays, sildenafil is gradually being found to have new uses, and many papers have reported that Viagra may have the effect of reducing the risk of Alzheimer's disease.

In 2021, a study published in the journal Nature Aging showed that people who took sildenafil had a 69% lower risk of Alzheimer’s disease than those who did not take it. The study covered more than 7 million people in the United States with an average age of around 71, of whom 116,000 took sildenafil[9].

A new study of nearly 670,000 men in the UK published in the journal Neurology on February 7, 2024 showed that people who took PDE5Is were less likely to develop Alzheimer's disease than those who did not. Compared with men who did not take sildenafil or similar drugs, men who took such drugs had an 18% lower risk of developing Alzheimer's disease. And those who used them more frequently (21-50 prescriptions) had a 44% lower risk of developing Alzheimer's disease [10].

Figure 3 A study published in the journal Neurology on February 7 [10]

Another study published on March 19 in the Journal of Alzheimer's Disease found that people who took sildenafil had a 30% to 54% lower chance of being diagnosed with Alzheimer's disease than those who did not take sildenafil, further confirming the findings of the Neurology article[11].

Figure 4 A study published on March 9 in the Journal of Alzheimer’s Disease [11]

But this is not the first time that this class of drugs has been linked to a reduced risk of Alzheimer’s disease – studies in animal models have shown since the late 1990s that PDE5I drugs can have a positive impact on cognitive abilities[12].

As mentioned above, the mechanism by which sildenafil treats ED has been studied quite thoroughly, but how this drug affects brain diseases such as Alzheimer's disease is still unknown. Scientists have proposed several potential mechanisms. For example, targets such as PDE5 are also present in other parts of the human body, including the brain, so increasing blood flow to the brain may reduce the likelihood of Alzheimer's disease to some extent [13].

In a 2021 Nature Aging study, Feixiong Cheng, lead researcher at the Cleveland Clinic, and his colleagues not only concluded from data analysis that the use of sildenafil is associated with a reduced risk of Alzheimer's disease, but also further explored the mechanism by which sildenafil affects Alzheimer's disease. They found that sildenafil can promote neuronal growth and reduce the expression of phosphorylated-tau in a neuronal model derived from induced pluripotent stem cells from AD patients. Phosphorylated tau protein is a type of protein that is closely related to Alzheimer's disease. It accumulates in the brains of Alzheimer's patients, which supports the potential benefits of sildenafil for AD from a mechanistic perspective. However, the authors also stated that the link between the use of sildenafil and a reduced incidence of AD cannot determine a causal relationship, which requires more experiments to verify [14].

Some researchers also believe that PDE5I drugs can strengthen the connections between brain neurons and synapses, because this process is partly dependent on cGMP. The brain stores memories by strengthening synaptic connections and helping connected neurons "talk" to each other. This may explain the link between PDE5I drugs and a reduced risk of Alzheimer's disease, because one of the symptoms of Alzheimer's disease is memory loss [13].

In addition, a 2019 study in the American Journal of Human Genetics revealed that people with genetic risk factors for type 2 diabetes are more likely to experience erectile dysfunction (ED) than those without these risk factors [14]. High blood pressure or type 2 diabetes are associated with the risk of developing Alzheimer’s disease. However, it is not known whether PDE5I drugs help improve cognition by controlling these diseases [15].

At present, none of these theories have been clearly confirmed, and the impact of PDE5I drugs on Alzheimer's disease still needs to be further explored. Some studies have also given different conclusions from the above. For example, a 2022 study of patients with pulmonary arterial hypertension (pulmonary arterial hypertension can be treated with PDE5I drugs) found that this drug was not associated with a reduced risk of Alzheimer's disease [16].

Figure 5 A study in patients with pulmonary arterial hypertension showed that PDE5I was not associated with a reduced risk of Alzheimer's disease [16].

All of the above studies have the same limitations: although the surveys covered a very large population, these studies were observational; that is, they only retrospectively compared the prevalence of different populations without in-depth exploration of other factors that may affect the risk of Alzheimer's disease. Therefore, it is impossible to draw a definite conclusion that PDE5I drugs affect the risk of AD. For example, the results of a 2024 study in the Journal of Alzheimer's Disease were pointed out that the authors did not take into account genetic or socioeconomic factors in their analysis, as well as the effects of the drug doses they used in the experiment.

What is the way forward for treating AD?

In previous big data retrospective studies, the population covered is often people with good cognitive function, who can have sex and have a need to take medication. In particular, most users of sildenafil are men, and whether sildenafil can improve women's cognitive ability has not been taken into consideration. These will bias the research results. In order to prove that sildenafil does have the effect of preventing Alzheimer's disease, or even to use it clinically to help people in need, scientists need to conduct clinical trials according to strict standards, rather than just the big data that proves the correlation mentioned above. More stringent clinical trial standards can include: recruiting subjects who meet the standards, setting up control groups and drug-treated groups in parallel, and matching the two groups of people in terms of age and gender with the people to be treated in the future. These will help to obtain more accurate experimental results.

Several clinical trials have evaluated the potential effects of PDE5I drugs on human cognition. However, these trials have been limited in size; for example, one trial included only 10 people. Some trials have only tested the short-term effects of treatment—measuring the cognitive effects of a single dose over the course of a day.[17]

To further prove that drugs like sildenafil can help prevent Alzheimer's disease, future trials may need to be conducted over a longer period of time, such as three to five years, and include patients clinically diagnosed with Alzheimer's disease. These results will be more convincing than previous studies.

At the same time, it is also important to look for clues to the treatment mechanism of Alzheimer's disease during clinical trials. There are many theories about the pathogenesis of Alzheimer's disease and the pathology is complex. If some new technologies are used to explore the changes in patient indicators during treatment, such as using brain imaging technology to measure changes in blood flow after patients take PDE5I drugs, these data may provide help for the future treatment of Alzheimer's disease.

Long-term trials also help scientists observe the side effects of long-term use of such drugs. If such drugs are really effective, there will be better improvement plans in the future. For example, for brain diseases such as Alzheimer's disease, the ability of drugs to pass through the blood-brain barrier is very important. Only when the drug molecules have enough accumulation in the brain can they exert better effects. Therefore, in subsequent research, scientists may be able to optimize this aspect to achieve better treatment effects [13].

If these drugs are eventually proven to be effective in preventing Alzheimer's disease, then like other old drugs that have been found to have new uses, their advancement into clinical use will be greatly accelerated, and more patients will benefit from them, as safety data has already been obtained at the human level.

There's still a long way to go before these little blue pills become prescription drugs that can actually prevent Alzheimer's disease.

References

[1] Scherzer ND, Le TV, Hellstrom WJG. Sildenafil's impact on male infertility: what has changed in 20 years? Int J Impot Res. 2019 Mar;31(2):71-73. doi: 10.1038/s41443-018-0067-x. Epub 2019 Mar 5. PMID: 30837720.

[2] Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006;5(8):689-702. doi:10.1038/nrd2030

[3] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20895ltr.pdf

[4] Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des. 2006;12(27):3439-3457. doi:10.2174/138161206778343064

[5] https://mp.weixin.qq.com/s/cIn2cxyf0QVOS5d45nlytw

[6] Nosengo N. Can you teach old drugs new tricks? Nature. 2016;534(7607):314-316. doi:10.1038/534314a

[7] Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010;11(9):1459-1466. doi:10.1517/14656561003792538

[8] Ahn HK, Lee YH, Koo KC. Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review. Int J Mol Sci. 2020;21(22):8540. Published 2020 Nov 12. doi:10.3390/ijms21228540

[9] 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. Nat Aging 1, 1175–1188 (2021). https://doi.org/10.1038/s43587-021-00138-z

[10] Adesuyan M, Jani YH, Alsugeir D, et al. Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study. Neurology. 2024;102(4):e209131. doi:10.1212/WNL.0000000000209131

[11] Gohel D, Zhang P, Gupta AK, et al. Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons. J Alzheimers Dis. 2024;98(2):643-657. doi:10.3233/JAD-231391

[12] Rutten K, Vente JD, Sik A, Ittersum MM, Prickaerts J, Blokland A. The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices. Behav Brain Res. 2005;164(1):11-16. doi:10.1016/j.bbr.2005.04.021

[13] https://www.livescience.com/health/medicine-drugs/does-viagra-reduce-the-risk-of-alzheimers-heres-what-we-know

[14] Bovijn J, Jackson L, Censin J, et al. GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology. Am J Hum Genet. 2019;104(1):157-163. doi:10.1016/j.ajhg.2018.11.004

[15] Sierra C. Hypertension and the Risk of Dementia. Front Cardiovasc Med. 2020;7:5. Published 2020 Jan 31. doi:10.3389/fcvm.2020.00005

[16] Desai RJ, Mahesri M, Lee SB, et al. No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer's disease and related dementia: results from the Drug Repurposing for Effective Alzheimer's Medicines study. Brain Commun. 2022;4(5):fcac247. Published 2022 Oct 4. doi:10.1093/braincomms/fcac247

[17] Samudra N, Motes M, Lu H, et al. A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer's Disease. J Alzheimers Dis. 2019;70(1):163-170. doi:10.3233/JAD-190128

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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