Repurposing drugs for the prevention of vascular dementia using evidence from drug target Mendelian randomization

Vascular dementia (VaD) is a devastating cerebrovascular disease with no disease-modifying treatments. Repurposing drugs for known risk factors could have clinical impact. Using Mendelian randomization, we proxied 46 lipid-lowering, antihypertensive and anti-inflammatory drug effects across five VaD outcomes: clinical diagnosis (N = 7,009 cases, N = 899,672 non-cases/controls) and neuroimaging features (max N = 50,559), white matter hyperintensity volume, fractional anisotropy, mean diffusivity and lacunar stroke diagnosis. Beta-1 adrenergic receptor indicated potential benefit (clinical diagnosis: odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.80-1.01; white matter hyperintensity volume: estimated causal effect = -0.03, 95% CI = -0.07-0.00; mean diffusivity: estimated causal effect = -0.18, 95% CI = -0.37-0.00; lacunar stroke: OR = 0.91, 95% CI = 0.80-1.03). Angiotensin-converting enzyme inhibition suggested increased VaD risk (OR = 1.12, 95% CI = 1.01-1.24). Findings remained largely null after multiple-testing correction. Here we show that although little evidence supported repurposing most lipid-lowering, antihypertensive and anti-inflammatory drugs for VaD prevention or treatment, beta-1 adrenergic receptor antagonism could be a promising repurposing candidate, but replication is needed as further data becomes available. Pharmacovigilance studies should examine angiotensin-converting enzyme inhibitors' potential to increase risk.