The Hard Truth: This "Little Blue Pill" Fights Alzheimer’s Disease?!

Viagra might actually prevent Alzheimer's disease. I know, I know, you're conflicted. You're intensely curious, but you're not sure if I'm being serious. There's a part of you thirsty to know more and another part afraid I'm going to hit you with a stream of innuendos without your consent. Okay, no more of that. And yes, I am serious. But before I make any more bad jokes, let's get right to the data in hand. Sorry, the data at hand. The paper I want to talk about was published in Nature Aging, and the researchers behind the paper began with an exploratory analysis. They were looking for predicted molecular interactions between existing drugs and their known effects and pathways involved in Alzheimer's disease. And one drug, sildenafil, also called Viagra, stood up. Darn it, I mean Viagra stood out. It stood out among the other drugs. But before I get to how Viagra might actually prevent Alzheimer's disease, and it's pretty fascinating science, let me slow down and engage in a little foreplay because I want to tell you the story about how this blockbuster drug came to be. There's a relevant point to make. In the late 1980s and early 1990s, scientists at Pfizer were working on a compound called sildenafil, also called Viagra. The goal was to treat angina, a type of chest pain caused by reduced blood flow to the heart. They hoped that the drug would relax blood vessels, improve circulation, and reduce the symptoms of cardiovascular disease, this angina pain. Sildenafil works by inhibiting an enzyme called phosphodiesterase 5, or PDE5 for short, which breaks down a compound called cGMP, which is a molecule involved and blood vessel relaxation. And the hope was that this would dilate coronary arteries and ease angina pain. But then, during the early clinical trials in 1991 and 1992, Pfizer researchers administered sildenafil to male volunteers, and the results were underwhelming. The drug didn't significantly improve angina. However, something else happened. A lot of the participants weren't giving the leftover medication back at the end of the trial. Some were even hoarding it, and the researchers were confused and wanted to know why. Why are the participants not giving this drug, which doesn't even work, back? One thing led to another, and in 1998, the US FDA approved Viagra as the first oral treatment for erectile dysfunction. The point of the story, the moral of the story, is sometimes molecules, drugs or otherwise, have unexpected effects, unexpected benefits, be that on the heart, the genitals, or the brain. And as it turns out, other phosphodiesterase enzymes like PDE5, which Viagra inhibits, are highly expressed in the brain and in other organs and play roles in various disease processes. So for example, Viagra, or sildenafil, is already prescribed to women for a condition called pulmonary hypertension, and that will become relevant later. So if Viagra truly reduces the risk of Alzheimer's disease, we would also expect to see that effect represented in large population datasets. Do we? Indeed we do. The researchers then perform multiple analyses on over 7 million individuals enrolled in Medicaid Advantage insurance and found that Viagra use was associated with— are you ready for this? A 69% reduced risk of Alzheimer's disease compared to non-Viagra users. That is the real number. I'm not even going to touch that joke. It's too easy. That was really the number. Anyway, to rule out confounding variables, they also compared Viagra against other commonly prescribed medications like diltiazem, clomipride, losartan, and metformin. It's not important you know what these medications are. The important point is every time Viagra was associated with a reduced risk of Alzheimer's disease compared to the comparison drug group. And the researchers also ran multiple subgroup analyses in people without heart disease, high blood pressure, or diabetes, and in groups with each of these conditions. And again and again and again and again, across the board, there appeared to be a protective association between Viagra use and lower Alzheimer's disease risk. The consistency of these findings and the replication across multiple subgroups, and the size of the risk reduction— that's 69%, and yes, size does matter— all point to results that are not only striking but potentially generalizable. So before we see if this actually generalizes even to women, how does it work? Given Viagra's primary use, one might assume the protective effects come from improved vascular health or change in vascular tone. There may be some effect there, but just because a medication was first FDA approved for one condition and credited on acting on a particular target or pathway doesn't mean that's all it affects. We already learned that lesson, remember? And interestingly, in their network analyses, the researchers found a hint that Viagra could inhibit a protein called glycogen synthase kinase 3 beta, or GSK3 beta. It's kind of poorly named, but GSK3 beta plays a role in Alzheimer's disease. It modifies tau proteins, contributing to the formation of phospho-tau neurofibrillary tangles, which are central to Alzheimer's pathophysiology. They choke the brain, they choke neurons, they are core to Alzheimer's disease. So in short, more GSK-3 beta activity can help drive Alzheimer's disease pathology, neurofibrillary tau tangles. And the researchers found that Viagra actually inhibited this GSK-3 beta enzyme in a pro-inflammatory context, providing a plausible biological mechanism to explain Viagra's association with reduced Alzheimer's risk. Now, at this stage, one more piece of evidence we might want is a demonstration of Viagra's direct effect on brain cells, on neurons, at least in vitro. So to explore this, the researchers derived neurons from patients with Alzheimer's disease and treated them with sildenafil, Viagra, in a dish. And the one molecular marker they were really interested in was phospho-Tau 181, a marker of this Alzheimer's disease pathology, the neurofibrillary tangles we talked about. And impressively, Viagra treatment significantly reduced phospho-Tau 181 levels in these Alzheimer's-derived neurons. That's really interesting. The takeaway here is there is now a clear relationship between Viagra use and lower Alzheimer's disease risk, plus a biological pathway that could explain this effect, and actually direct evidence that Viagra does reduce the formation of a core neuropathology, phospho-tau, of Alzheimer's disease. And guess what? This is not just for men. As I mentioned earlier, a compound can have many uses, and while Viagra is best known for treating erectile dysfunction, In men, the same medication can be used off-label for other conditions, including pulmonary hypertension, in women. So what this provided was actually a population, a pool of women to study the effects of sildenafil, commonly known as Viagra, on Alzheimer's disease risk. So the question: does Viagra protect against Alzheimer's disease risk in women as well as men? And in short, the answer is yeah, it appears so. Admittedly, the overall reduction in Alzheimer's disease risk was smaller in women than men. It's not clear whether this represents a true sex difference or if it's simply an artifact of the smaller sample size for women as compared to men and the fact that lower doses of sildenafil, the medication, are typically given to women for pulmonary hypertension as compared to men for erectile dysfunction. So time and more data will tell. But wrapping up, where does all this leave us? We now have large-scale population data, biological biological plausibility, and direct evidence at a cellular level, all pointing towards a surprising conclusion. Viagra may do more than improve blood flow below the belt. It also might protect the brain. Of course, we will need randomized controlled trials to confirm causality, but in the meantime, the science is raising— it's raising eyebrows. Raising eyebrows. Get your head out of the gutter. Anyway, I hope you found this interesting. Stay curious.