Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 14, 2025
Abstract Phosphodiesterase−5 (PDE5) inhibitors have gained interest as a potential treatment for dementia. However, current evidence is limited to observational and pre-clinical studies. We conducted drug-target Mendelian randomization (MR) analysis investigate the on-target effects of pharmacological PDE5 inhibition on dementia subtypes related phenotypes. selected variants from around PDE5A locus associated with diastolic systolic blood pressure, well circulating levels, create three instruments genetically proxied inhibition. Using two-sample MR, we validated against erectile dysfunction pulmonary arterial hypertension before assessing their associations subtypes, dementia-related proteins, neuroimaging traits. After correcting multiple comparisons, inhibition, per one SD lower in was higher odds Alzheimer’s disease (OR 1.09, 95% CI 1.07–1.11) Lewy body 1.32, 1.23–1.41), but trend towards vascular across all instruments. Genetically both beneficial adverse brain MRI This included volumes white matter hyperintensities (SD change − 0.035, 0.025, 0.045), indicating benefits, also reduced other structures, including thalamus, suggesting effects. concentrations several proteins implicated pathophysiology. Our findings suggest that while may be risk dementia, possibly by preventing hyperintensities, it increase warranting further investigation clinical trials.
Language: Английский