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Phosphodiesterase inhibitors and dementia

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia (1).

Phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators (1)

  • in animals PDE5 inhibitors enhance synaptic function and cognitive ability
    • primary clinical effects of PDE5I are a result of raised cyclic guanosine monophosphate (cGMP), a secondary messenger that is degraded by the phosphodiesterase enzyme (PDE) (2)
      • studies have shown low levels of cGMP in tandem with raised levels of PDE in the brains of people with Alzheimer's disease
  • is evidence that in humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease (1)

A UK cohort study of men aged ≥40 years with a new diagnosis of erectile dysfunction (n=269,725) found the initiation of PDE-5 inhibitors was associated with a decreased risk of Alzheimer’s disease compared with non-users (adjusted HR 0.82, 95% CI 0.72–0.93) (2):

  • sensitivity analysis with a 1-year lag period (excluding those with less than 1 year of follow-up after cohort entry) supported the primary findings (HR 0.82, 95% CI 0.72–0.94), but the results differed with the inclusion of a 3-year lag period (HR 0.93, 95% CI 0.80–1.08)
    • study authors state that this highlights the need to explore the optimal lag period, and they call for a randomised controlled trial including both men and women, exploring various PDE-5 inhibitor doses, to confirm their findings in a wider population

Reference:

  • Hainsworth AH, Arancio O, Elahi FM, Isaacs JD, Cheng F. PDE5 inhibitor drugs for use in dementia. Alzheimers Dement (N Y). 2023 Sep 25;9(3):e12412.
  • Adesuyan M et al.Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease
    A Cohort Study. Neurology February 7th 2024.

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