| Summary: | Abstract Alzheimer's disease and related dementias (ADRD) remain a major health‐care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration–approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real‐world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half‐life, and off‐target effects. HIGHLIGHTS Potent phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators. In animals PDE5 inhibitors enhance synaptic function and cognitive ability. In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease. Licensed PDE5 inhibitors have potential for repurposing in dementia. Prospective clinical trials of PDE5 inhibitors are warranted.
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