Genetically Proxied Phosphodiesterase Type 5 (PDE5) Inhibition and Risk of Dementia: A Drug Target Mendelian
Stephen O Brennan1,2, Alexander C Tinworth3
1University of Galway, Galway, Ireland. stephen.o.brennan@universityofgalway.ie.
Molecular Neurobiology
|February 14, 2025
Summary
Phosphodiesterase-5 (PDE5) inhibitors show mixed results for dementia risk. While potentially lowering vascular dementia risk, they may increase Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Phosphodiesterase-5 (PDE5) inhibitors are being explored for dementia treatment.
- Current evidence is limited to observational and pre-clinical studies.
- Investigating on-target effects of PDE5 inhibition on dementia is crucial.
Purpose of the Study:
- To investigate the causal effects of pharmacological PDE5 inhibition on dementia subtypes using drug-target Mendelian randomization (MR).
- To assess associations with dementia-related proteins and neuroimaging traits.
Main Methods:
- Utilized a two-sample Mendelian randomization (MR) approach.
- Selected genetic variants around the PDE5A locus associated with blood pressure and PDE5A levels as instrumental variables.
- Validated instruments against erectile dysfunction and pulmonary arterial hypertension.
Main Results:
- Genetically proxied PDE5 inhibition was associated with increased odds of Alzheimer's disease (OR 1.09) and Lewy body dementia (OR 1.32).
- A trend towards lower odds of vascular dementia was observed.
- Associated with reduced white matter hyperintensities but also decreased volumes in other brain structures like the thalamus.
Conclusions:
- PDE5 inhibition may have a protective effect against vascular dementia, potentially by reducing white matter hyperintensities.
- However, it may be linked to an increased risk of Alzheimer's disease and Lewy body dementia.
- Further research is warranted before considering clinical trials for dementia.
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