TY - JOUR
T1 - Phosphodiesterase-5 Inhibition and Alzheimer's Disease Risk
T2 - A Mendelian Randomisation Study
AU - Alcalde-Herraiz, Marta
AU - Woolf, Benjamin
AU - Xie, Junqing
AU - Anderson, Emma
AU - Gill, Dipender
AU - Tzoulaki, Ioanna
AU - Winchester, Laura M.
AU - Yarmolinsky, James
AU - Prieto-Alhambra, Daniel
AU - Newby, Danielle
N1 - Publisher Copyright:
© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105018688182
U2 - 10.1111/acel.70265
DO - 10.1111/acel.70265
M3 - Article
C2 - 41078087
AN - SCOPUS:105018688182
SN - 1474-9718
VL - 24
JO - Aging Cell
JF - Aging Cell
IS - 12
M1 - e70265
ER -