Phosphodiesterase‐5 Inhibition and Alzheimer's Disease Risk: A Mendelian Randomisation Study

Journal article

While preclinical studies suggest that Phosphodiesterase 5 (PDE5) inhibition may reduce cognitive impairment, findings from observational studies on whether PDE5 inhibitors reduce Alzheimer's disease (AD) risk have been inconsistent. We performed a two‐sample cis‐Mendelian Randomisation (MR) analysis to estimate the causal effect of PDE5 inhibition on AD risk. The analysis was performed across four different genome‐wide association studies (GWAS) of AD to enhance reliability through triangulation. Additionally, a sex‐stratified MR analysis using data from UK Biobank was performed to assess potential sex‐specific effects. No evidence of a causal association between PDE5 inhibition and AD risk was found in the main analyses. Similar findings were obtained in the sex‐stratified analysis. Our study uses genetic data to triangulate the evidence and suggests that PDE5 inhibitors are unlikely to decrease the risk of AD. Further research is needed to thoroughly understand the impact of PDE5 inhibitors on the risk of Alzheimer's disease.

Authors: Alcalde‐Herraiz, M; Woolf, B; Xie, J; Anderson, E; Gill, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Aging Cell
• Article number: e70265
• Publication date: 2025-10-13
• Acceptance date: 2025-09-29
• DOI: 10.1111/acel.70265
• EISSN: 1474-9726
• ISSN: 1474-9718
• Language: English
• Keywords: dementia; sildenafil; Mendelian randomisation; phosphodiesterase‐5; Alzheimer's disease