Conflicting evidence on PDE5i: No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer’s disease and related dementia: results from the Drug Repurposing for Effective Alzheimer’s Medicines study 2022
A recent Israeli study also found no protective effect for tadalafil vs alpha-blockers in BPH: Phosphodiesterase-5 Inhibitors and Dementia Risk: A Real-World Study 2024
The issue with PDE5 inhibitors is the lack of a good comparator and potential confounders (someone who gets prescribed viagra has a more active social and sexual life, which is associated with healthspan): Phosphodiesterase-5 Inhibitors and Dementia Risk: Confounding by Indication in Real-World Studies 2024
It might not be a class property but a specificity of sildenafil: Phosphodiesterase-5 inhibitors use and the risk of alzheimer’s disease: a systematic review and meta-analysis 2024: “Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31–0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant.”
A recent study also found a protective effect (Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study 2024) but they note “Last, because of the limitations of our database, we cannot rule out the effect of unmeasured confounding. We were unable to account for levels of physical and sexual activity, which may confer a level of benefit in AD risk and be predictive for PDE5I exposure.”.
In this study, over 18 years (!), I would expect the difference between the two curves to become wider and wider, it’s not the case:
Here, as well, the potential protective effect only applies to sildenafil:
As they note: “Evidence from pharmacokinetic studies have shown that the PDE5Is, sildenafil and tadalafil, both cross the blood–brain barrier, with sildenafil demonstrating greater permeability.”
(Of note, the ITP chose to test sildenafil and not tadalafil…)
I would also expect regular users (>50) to have even less AD risk, but it doesn’t seem to be the case:
And surprisingly, it’s only protective in people >70yo?! If the protection was real, I would expect that the sooner you start, the better, right?:
They also don’t find any benefit “Among individuals without hypertension or diabetes”. 
Then we have this Mendelian randomization preprint (
) by a researcher from Oxford University: Genetically proxied PDE5 inhibition and risk of dementia: a drug target Mendelian randomisation study 2024
In contrast to evidence from observational studies, our findings indicate that inhibition of PDE5 is associated with a higher risk of dementia and an unfavourable neurocognitive profile. This risk should be further investigated prior to clinical trials of pharmacological PDE5 inhibition for the treatment and prevention of dementia.
My conclusion from all the above:
- Tadalafil is not neuroprotective
- Sildenafil: still an open question, but probably not.
- If the MR preprint is correct, tadalafil and sildenafil might even be neurotoxic.
Thoughts @DrFraser?
