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

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer's disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer's disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity score matching. Across four separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors;hazard ratio (95% confidence interval): 0.99 (0.69-1.43), 1.00 (0.71-1.42), 0.67 (0.43-1.06), and 1.15 (0.57-2.34). We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer's disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer's disease and related dementia. Desai et al. report no association between initiation of phosphodiesterase-5 inhibitors and risk of dementia in a rigorous pharmacoepidemiologic analysis using robust design principles including restriction by the same underlying indication of pulmonary hypertension and an equivalent comparator group of endothelin receptor antagonists to address measured and unmeasured confounding.