Drugs taken to treat erectile dysfunction have once again been tied to a reduced risk of Alzheimer's disease.
A new study of almost 670,000 men in the U.K., published Feb. 7 in the journal Neurology, revealed that those who take so-called phosphodiesterase 5 inhibitors (PDE5I) — which include Viagra (generic name sildenafil) — may have a lower risk of developing this common form of dementia than men of the same age who don't take the drugs. Another study, published March 19 in the Journal of Alzheimer's Disease, found that people who took sildenafil were 30% to 54% less likely to be diagnosed with Alzheimer's disease compared to those who didn't, adding to this idea.
But this isn't the first time that drugs like the "little blue pill" have been linked to this reduced dementia risk — since the late 1990s, rodent studies have suggested that PDE5I drugs could have beneficial effects on cognition, and in 2021, a study published in the journal Nature Aging suggested that taking Viagra was associated with a 69% reduced risk of Alzheimer's. That 2021 study included more than 7 million people in the U.S. who on average were around 71 years old, 116,000 of whom took Viagra.
PDE5I drugs like Viagra work by increasing blood flow to the erectile tissues of the penis. They do this by preventing the breakdown of a signaling molecule called cyclic guanosine monophosphate (cGMP), which keeps smooth muscles within the penis relaxed. This relaxation allows blood to flow into the erectile tissue — the corpus cavernosum — as its blood vessels dilate upon sexual arousal. When cGMP gets broken down too quickly, the erection can't be maintained.
Related: Viagra alternatives? Study of mouse erections hints at new ways to treat erectile dysfunction
While Viagra's effects on the penis are well understood, it's unknown how this and similar drugs may influence brain disorders such as Alzheimer's. However, several potential mechanisms have been proposed.
Other than influencing erections in the penis, PDE5I drugs dilate blood vessels throughout the body, including in the brain, Dr. Sevil Yasar, an associate professor of medicine at Johns Hopkins University, told Live Science. Indeed, Viagra was originally developed to treat high blood pressure and chest pain. It's therefore possible that increased blood flow in the brain may somehow reduce the burden of Alzheimer's, she said.
In the 2021 Nature Aging study, Feixiong Cheng, a principal investigator at the Cleveland Clinic, and colleagues found that Viagra boosted the growth of brain cells that had been grown from the stem cells of patients with Alzheimer's. The drug also turned down the production of proteins associated with the disease — namely, phosphorylated tau, which accumulates in the brains of people with Alzheimer's.
Increased blood flow to the brain that results from these drugs might therefore help clear these proteins in some way, Cheng told Live Science.
Another explanation could be that PDE5I drugs strengthen the connections, or synapses, between neurons in the brain, as this process partially relies on cGMP, Atticus Hainsworth, a reader in cerebrovascular disease at St George's, University of London, told Live Science. The brain stores memories by strengthening synapses, helping linked neurons "talk" to one another. This could explain the link between PDE5I drugs and a reduced risk of Alzheimer's, which causes memory loss.
In addition, people with high blood pressure or type 2 diabetes have a higher risk of experiencing erectile dysfunction and of developing Alzheimer's, compared with people without either condition. So it could be that erectile-dysfunction drugs are helping to manage these other conditions, rather than directly targeting the causes of Alzheimer's, Yasar said.
For now, though, none of these theories has been definitively proved — in fact, it's still unclear whether PDE5I drugs have any effect on Alzheimer's risk.
In 2022, for example, a study in people with pulmonary arterial hypertension — a form of high blood pressure in the lungs that can be treated with PDE5I drugs — found that the medications were not associated with a reduced risk of Alzheimer's.
A big issue is that the largest studies to date have been observational, meaning they retroactively compared the rates of disease between different people without accounting for other factors that could affect people's Alzheimer's risk. Such studies can't definitely prove that erectile-dysfunction drugs influence the risk. For example, the findings of the 2024 Journal of Alzheimer's Disease study may have been skewed by genetic or socioeconomic factors which weren't considered by the authors in their analyses, and by the doses of drug they used in lab-dish experiments.
Related: Erectile dysfunction risk may rise on lengthy space missions, rat study reveals
To do so, scientists would need to conduct a gold-standard clinical trial with comparison groups who don't take the drug but are matched to those who do in other ways, such as age and sex. This would help ensure that other lifestyle factors or medical conditions don't skew the results.
For example, "it could be that the people who are still cognitively well enough to have sex and want the drugs are biasing the [study] population," Hainsworth said.
A few clinical trials have assessed the potential cognitive effects of PDE5I drugs in humans. However, these have been limited in size; one trial included only 10 people, for instance. Some have tested only the short-term impacts of the treatment — for example, with the cognitive effects of a single dose measured over the course of a day.
To get closer to proving that erectile-dysfunction drugs can help prevent Alzheimer's, future trials would need to run for potentially three to five years and include people with clinically confirmed Alzheimer's diagnoses, Yasar said. This would go beyond relying on, say, insurance claims data, as previous observational studies have done, she said.
It would also be important to look for telltale markers of Alzheimer's disease during the trials, using brain imaging to measure changes in a person's blood flow after they took PDE5I drugs, she added.
Long-term trials would allow scientists to look out for any long-term side effects of taking erectile-dysfunction drugs. Such side effects could stem from taking a drug that reduces the pressure of blood flowing through your arteries, Francesco Tamagnini, a lecturer in pharmacology at the University of Reading in the U.K., told Live Science.
On a mechanistic level, the drugs may need to be modified slightly so they are more likely to accumulate in the brain, to achieve the most robust effects, Tamagnini said.
Future trials could also include women, as well as men, to see if similar cognitive effects are seen in them, Hainsworth said. Currently, Viagra is only approved by the U.S. Food and Drug Administration (FDA) to treat erectile dysfunction in men. Several early studies have investigated whether it could be used to treat sexual dysfunction in women, but with conflicting conclusions about effectiveness.
If these drugs eventually turn out to be an effective guard against Alzheimer's, they could fuel the fire of research striving to repurpose approved drugs for other uses. This is happening with the diabetes drug metformin, for example, which doctors are trying to repurpose for cancer and heart disease, Tamagnini said. As these drugs are already licensed for use in humans, this could speed up the drug-development process, he said.
For the little blue pill, though, there's a long way to go before it would be prescribed as dementia prevention.
This article is for informational purposes only and is not meant to offer medical advice.
Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to community@livescience.com with the subject line "Health Desk Q," and you may see your question answered on the website!
Editor's note: This story was last updated on March 27, 2024, to include information on the Journal of Alzheimer's Disease study. The article was first published on Feb. 16, 2024.
