The odds are five percent that someone in the US will develop Alzheimer's disease under the age of 65 but increases to fifty percent for those 85 and over. 1 According to the Alzheimer's Association: Between 2000 and 2019, deaths from heart disease have decreased 7.3%, while deaths from Alzheimer's have increased 145%. 

• More than 6 million Americans are living with Alzheimer's

• By 2050. nearly 13 million people may suffer from Alzheimer's

• In the US, Alzheimer's and dementia deaths have increased 16% during covid

• 1 in 3 dies with Alzheimer's or dementia. It kills more than breast and prostate cancers combined

• In 2021, Alzheimer's and dementia will cost the country $355 billion

• More than 11 million Americans provide unpaid care for people with Alzheimer's and dementia

• In 2020, caregivers provided an estimated 15.3 billion hours of care valued at nearly $257 billion 2

Plaques and Tangles

Scientists have recognized that Alzheimer's disease is akin to the cells in the Brain ceasing to clean and maintain themselves properly. As a result, Plaques and tangles develop, parts of the brain start dying off, and cognition suffers. The two main changes seen in the brains of Alzheimer's patients are plaque formations and tangles of tau proteins. The plaques are deposits of a protein fragment called beta-amyloid that build up between nerve cells. The tangles are twisted collections of a protein called tau.

Nitric Oxide, cGMP and the Brain

Warning: skip this part if you don't like geek-speak

The amino acid arginine is converted into nitric oxide by nitric oxide synthase, which promotes nitric oxide production. Nitric oxide is a small cell-permeable gas molecule that diffuses across the plasma membrane, promotes blood flow, and activates soluble guanylyl cyclase, converting guanosine triphosphate into cGMP. This pathway is critical for healthy brain function and is called the NOS/NO/cGMP pathway. Unfortunately, NOS activity is significantly impaired in patients with Alzheimer’s disease; subsequently, the NOS/NO/cGMP pathway activity is severely damaged, producing inadequate amounts of cGMP, poor blood flow, plaques, and other problems. In the brains of Alzheimer's patients, Phosphodiesterase 5 (PDE5) is found in abundance. Unfortunately, PDE5 breaks down cGMP, exacerbating the issues mentioned above. 3

Sildenafil/Viagra 

Pfizer originally developed the sildenafil compound to treat high blood pressure and chest pain due to heart disease. However, during the heart clinical trials, researchers discovered that the drug was more effective at inducing erections than treating chest pain. As a result, Pfizer finally had the drug approved in 1998 to treat erectile dysfunction. We know it as Viagra. 4 Viagra was the first PDE5 inhibitor of its kind. 

A 2017 review by Heckman and colleagues opined that PDE5 seemed to hold the most promise for treating Alzheimer's disease. 5 So, in 2017, researchers found that twelve Alzheimer's disease patients had improved brain blood flow and metabolism after being given 50 mg of sildenafil. 6 Since sildenafil increases nitric oxide and nitric oxide enhances blood flow; these results are unsurprising. Previous studies have suggested that therapeutic strategies to reduce cardiovascular diseases may reduce the prevalence of Alzheimer's disease. Indeed, among the 14 FDA-approved cardiovascular drugs identified, there are currently nine drugs under preclinical or clinical trials for Alzheimer's disease. 7 In 2019, researchers found that 50mgs of sildenafil improved brain function in ten Alzheimer’s disease. 8 Again, these results make sense because the upregulation of cAMP by sildenafil enhances brain function. 

The New Study

Researchers developed an "endophenotype disease module-based methodology for Alzheimer's disease drug repurposing." First, they identified Viagra/sildenafil for its potential use as a preventative because it increases blood flow. Decreased brain blood flow often occurs with Alzheimer's and is one of the leading causes of age-related cognitive impairment. Sildenafil has been shown to significantly improve cognition and memory in a rat model of vascular dementia. In addition, sildenafil treatment also decreases tau protein buildup in mice models. They then looked at 7.23 million insurance claims and compared sildenafil to the four known therapies for Alzheimer's disease: Diltiazem, Losartan, Glimepiride, and Metformin. The graph below compares the six-year survival rate of the subjects taking sildenafil compared to those on no medications, diltiazem, Losartan, Glimepiride, and Metformin.

As you can see, in every comparison, the subjects on sildenafil had a significantly better chance of not developing Alzheimer's disease. The vertical measures the percentage of subjects without Alzheimer's disease. Notice that it starts at .92 which makes the graphs diverge more dramatically. The horizontal going from left to right is the number of years (6) the study lasted. The authors conclude that sildenafil provides a 69% better chance of avoiding Alzheimer's disease. Unfortunately, this is not the case; let me explain.

Tricky Statistics

I included some additional numbers at the bottom of the graph. HR is short for hazard ratio. The hazard ratio tells you the risk of developing Alzheimer's disease at any point in time. It is similar to the relative risk ratio, but the relative risk ratio is the cumulative risk over the entire time of the study. I have written before about their use as an oversell to the unsuspecting public. For example, a hazard ratio of 3 means that three times the number of events are seen in the treatment group at any point in time. But if three out of one hundred thousand develop a disease without medication and only one out of one hundred thousand who do while on the pill, there is hardly any real difference between the two groups, but the drug companies will sell their drug as being three times better than not taking it!

The CI number is the confidence interval. The 95% confidence interval lets us know that the researchers are confident that 95 out of 100 times their estimates will fall between the upper and lower values specified by the confidence interval. The higher the number, the more believable the study. So, this particular study is a good one as far as CI is concerned. 

The P-value is the probability that the findings are not random. The lower the P-value, the better the odds are that the results are NOT unexpected, which is a good thing. As we can see, the P-values are minuscule, meaning there is a substantial likelihood that sildenafil is making a real difference.

The Real Numbers

Looking at the graph above, at the end of six years, 99 out of 100 subjects had no Alzheimer's disease while taking sildenafil versus 95 out of 100 who were not. This is not a 69% prevention rate the authors claim. They are not lying, but they are using hazard ratios which mislead. The HR is .31 for sildenafil versus no other medication. 1 minus .31 is .69. So, the researchers are fooling us into thinking taking Viagra will decrease our chances of developing Alzheimer's disease by 69 percent. 

A better way to tell what is going on is to compare the fact that after six years, 95 out of 100 people in the control group all had no Alzheimer's, but five did. Compared to the people on sildenafil, only one out of 100 got Alzheimer's disease. The accurate comparison is that taking 50mg of sildenafil over six years will drop your chances of developing Alzheimer's disease from five percent down to one percent.

The Bottom Line

Taking sildenafil could drop your chances of developing Alzheimer's disease by four percent, which is still beneficial. However, six million Americans under 65 have the disease. Lowering this population by four percent means 150,000 fewer people will get Alzheimer's disease if it is found that sildenafil works and is approved for use in preventing Alzheimer's disease.

Conclusion

I believe this was a well-done study, but it is a demographic study. As such, the researchers could not account for many variables. Nevertheless, they admit all the shortcomings in their paper. Population-based observational studies cannot build causal relationships between sildenafil use and beneficial clinical response of Alzheimer's disease. The authors acknowledge that the association between sildenafil usage and decreased incidence of Alzheimer's disease does not establish any causality. The authors are now designing a randomized, double-blind, placebo-controlled study to show an actual cause and effect between sildenafil and Alzheimer's disease. Such studies are held in the highest esteem by the scientific community. It will be nice to see their results, especially in the over-85 population. Since fifty percent of them have Alzheimer's disease, even a modest result could stop millions of cases. In the meanwhile, the best prevention against Alzheimer’s disease and many other killers is good sleep, avoiding processed foods, getting sunshine, staying active, and nurturing caring relationships.