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 (MR), we proxied 46 lipid-lowering, antihypertensive, and anti39 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 (WMH); fractional anisotropy; mean diffusivity; and lacunar stroke diagnosis. Beta-1 adrenergic receptor (ADRB1) indicated potential benefit (clinical diagnosis: OR=0.90, 95%CI=0.80–1.01, WMH: β=-0.03, 95%CI=-0.07–0.00, mean diffusivity: β=-0.18, 95%CI=-0.37–0.00, lacunar stroke: OR=0.91, 95%CI=0.80–1.03). Angiotensin-converting enzyme (ACE) 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 while little evidence supported repurposing most lipid-lowering, antihypertensive and anti-inflammatory drugs for VaD prevention or treatment. ADRB1 antagonism could be a promising repurposing candidate, but replication is needed as further data becomes available. Pharmacovigilance studies should examine ACE inhibitors’ potential to increase risk.