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

Abstract

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.

Keywords: Alzheimer’s disease; PDE5 inhibitors; cohort study; dementia; repurposing.

Graphical abstract

Figure 1

Relative risk of Alzheimer’s disease and related dementia in patients treated with PDE5 inhibitors versus ERAs before and after 1:1 propensity score matching, Medicare data 2007–2018. Analysis 1: ‘As-treated’ follow-up approach; Analysis 2: ‘As-started’ follow-up approach incorporating a 6-month induction period; Analysis 3: Incorporating a 6-month ‘symptom to diagnosis’ period’ and Analysis 4: Alternate outcome definition (See Methods for additional description of analytic approach).

Figure 2

Cumulative incidence of Alzheimer’s disease and related dementia in patients treated with PDE5 inhibitors versus ERAs after 1:1 propensity score matching, Medicare data 2007–2018. Analysis 1: ‘As-treated’ follow-up approach; Analysis 2: ‘As-started’ follow-up approach incorporating a 6-month induction period; Analysis 3: Incorporating a 6-month ‘symptom to diagnosis’ period’ and Analysis 4: Alternate outcome definition (See Methods for additional description of analytic approach).

Figure 3

Relative risk of Alzheimer’s disease and related dementia in patients treated with PDE5 inhibitors versus ERAs after 1:1 propensity score matching within pre-specified subgroups, Medicare data 2007–2018. Analysis 1: ‘As-treated’ follow-up approach; Analysis 2: ‘As-started’ follow-up approach incorporating a 6-month induction period; Analysis 3: Incorporating a 6-month ‘symptom to diagnosis’ period’ and Analysis 4: Alternate outcome definition (See Methods for additional description of analytic approach).

Figure 4

Effect of sildenafil on cell culture-based phenotypic assays. (A) Levels of exogenous Aβ_1–42 in the supernatant in BV2 microglial cells and (B) in H4-hAPP overexpressing neuroglioma cells after 24 h treatment with sildenafil. Sildenafil at the lowest concentration (0.10 µM) significantly increased levels of Aβ_1-42. Levels of inflammatory cytokines (C) TNF-α, (D) IL-12p70, (E) IL-1β in the supernatant of BV2 (microglial) cells after 24 h LPS stimulation and sildenafil treatment. Sildenafil at the highest concentration (10 µM) significantly reduced secretion of TNF-α and IL-12p70; sildenafil at the highest and lowest concentrations (10 and 0.10 µM, respectively) significantly reduced secretion of IL-1β. Error bars in all bar graphs indicate group mean + standard deviation (SD). Individual values are shown as dots (n = 6 per group). Each dot represents a technical replicate. Group differences comparing sildenafil-treated cells to the VC or LPS control were evaluated using the one-way ANOVA test followed by Dunnett’s multiple comparison test. Asterisks indicate significant differences between groups: * P < 0.05; ** P < 0.01; *** P < 0.001. VC, vehicle control (0.1% DMSO); LPS, lipopolysaccharide.