Monday, December 20, 2021

Studying sildenafil's potential to prevent Alzheimer's disease

 - Jennifer Middleton, MD, MPH

As the controversy over aducanumab's FDA approval for Alzheimer's disease continues, another potential treatment for Alzheimer's has been garnering attention. Using a complex gene-mapping technique, a team of U.S. researchers identified sildenafil (Viagra, Revatio), out of a group of more than 1,600 FDA approved medications, as having the potential to target both amyloid and tau protein formation. Further case-control analysis demonstrated a decreased risk of Alzheimer's among individuals who had received a sildenafil prescription compared to those who had not.

The researchers began with the hypothesis that an effective Alzheimer's medication should target both amyloid and tau, given the failure to date of attempts to create effective, separate anti-amyloid and anti-tau therapies:

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” said Dr. Cheng [the study's lead investigator]. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”

The researchers then used a "large gene-mapping network" which "integrated genetic and other biologic data" and scored each medication based on its effect on amyloid and tau, with higher scores for medications that targeted both. When sildenafil received the top score, the researchers then analyzed over 7 million insurance claims records and found that "sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio 0.31, 95% confidence interval 0.25–0.39, P < 1.0 × 10–8)." The study team correctly notes that "[t]he association between sildenafil use and decreased incidence of AD does not establish causality, which will require a randomized controlled trial," which the study team is currently planning.

The implications of this "big data" approach to identifying novel treatments among approved FDA medications ("drug repurposing") is tantalizing, and the sildenafil/Alzheimer's research team is reportedly already investigating applying this approach to Parkinson's disease and amyotrophic lateral sclerosis. Perhaps this study portends a new wave of research to benefit patients with diseases that, to date, have limited therapeutic options. 

None of the study researchers is advising the use of sildenafil yet for Alzheimer's disease, though you can find an overview of currently approved treatment options (minus aducanumab, which was not yet available at the time of publication) in this AFP article on "Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms." There's also an AFP By Topic on Dementia if you'd like a more in-depth review.