Probably not, but there is interesting speculation. Viagra/ sildenafil is widely prescribed to treat erectile dysfunction. By inhibiting phosphodiesterase 5 (PDE-5), it increases cyclic guanosine monophosphate (cGMP) and promotes vasodilation.
Normally an increase in cGMP would suppress nitric oxide (NO) by negative feedback. But sildenafil interrupts this mechanism so that NO remains available to stimulate even more cGMP. The consequent vasodilation increases blood flow not only to the penis, but also to the brain.
Moreover, regions of the cerebral cortex in Alzheimer brains have been found to have low cGMP and high PDE-5 levels, suggesting a role for sildenafil. The reason low cGMP may matter in Alzheimer is because cGMP normally activates peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). In turn, PGC1α limits the production of amyloid beta, the infamous compound that accumulates in the cortex and hippocampus of Alzheimer brains.
Indeed higher levels of PGC1α seem to have several benefits for neuronal gene expression and metabolism. But studies suggest it is not as simple as maximizing PGC1α via cGMP. The latter nucleotide is a versatile ‘second messenger’ and at a certain concentration starts to degrade cyclic adenosine monophosphate (cAMP), which in turn reduces PGC1α. In vitro and rodent studies suggest that increasing PGC1α requires a sufficiently low dose of sildenafil.
Cool right? But there are reasons for skepticism.
- While amyloid beta is generated in Alzheimer dementia, we still don’t know that reducing it prevents or cures Alzheimer. Take Aduhelm, the controversial biologic approved in 2021 by the FDA for Alzheimer. The drug has been shown to reduce amyloid beta, but only one of the two clinical trials associated this with a small cognitive benefit, and both trials were stopped prematurely due to projected futility. (Not to mention that around 40% of those taking Aduhelm developed cerebral edema and/or hemorrhage. Its FDA approval is a remarkable story for another day).
- Postmortem analysis of Alzheimer brains routinely demonstrate vascular disease. If sildenafil has a role here, it may simply be in promoting cerebral perfusion. Additionally, brain insulin resistance has been implicated in Alzheimer. If sildenafil improves insulin sensitivity (as suggested by a randomized controlled trial involving around 50 people with prediabetes), then in theory it could help prevent Alzheimer via glycemic control.
What else improves vascular endothelial function, insulin sensitivity, and cognition? Unprocessed, plant-based eating patterns. We can keep an open mind to the possible utility of low-dose sildenafil and its effect on PGC1α regulation, but at the end of the day it is unlikely to outperform basic interventions for metabolic health like eating salad and taking walks.
https://content.iospress.com/articles/journal-of-alzheimers-disease-reports/adr200166#ref125
https://jamanetwork.com/journals/jamaneurology/fullarticle/2786606
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