Repurposing drugs for the prevention of vascular dementia: Evidence from drug target Mendelian randomization

Importance

Vascular dementia (VaD) is a devastating cerebrovascular disease with no disease-modifying treatments available. Repurposing existing drugs for VaD risk factors could have an important clinical impact.

Objective

To determine whether lipid-lowering, anti-hypertensive, or anti-inflammatory drug targets affect the risk of vascular dementia using Mendelian randomization.

Design

Evidence suggests that higher cholesterol and blood pressure are associated with increased VaD risk, and inflammation is thought to play a key role in pathogenesis. Two-sample MR was conducted using cis- acting genetic variants in genes encoding each drug target, and data on five VaD-related outcomes. Instrument performance was assessed with positive controls (coronary artery disease, heart failure, stroke and rheumatoid arthritis).

Setting

Summary-level genetic data

Participants

Publicly available genetic association data from large cohorts of European ancestry. To maximize the sample size for vascular dementia risk as an outcome, we conducted a meta-analysis of case-control data from FinnGen & MEGAVCID.

Exposures

Genetically proxied drug effects for 46 lipid-lowering (n=17), antihypertensive (n=18), and anti-inflammatory (n=11) targets.

Main Outcomes and Measures

Odds ratios/betas and 95% CIs for VaD outcomes (clinical diagnosis, white matter hyperintensity volume, fractional anisotropy, mean diffusivity and lacunar stroke diagnosis) were estimated per 1-unit change in the exposure.

Results

For VaD risk, N=7,009 cases and N=899,672 controls were used. Neuroimaging outcome datasets included a maximum of N=50,559 participants. Beta-1 adrenergic receptor (ADRB1) was the only target for which there was consistent, albeit modest, evidence of benefit for four out of the five outcomes (clinical diagnosis: OR= 0.90, 95%CI 0.80 to 1.01, white matter hyperintensities: β= -0.03, 95%CI -0.07 to 0.00, mean diffusivity: β= -0.18, 95%CI -0.37 to 0.00, lacunar stroke: OR= 0.91, 95%CI 0.80 to 1.03). Angiotensin-converting enzyme (ACE) inhibition was suggested to increased VaD risk (OR= 1.12, 95%CI 1.01 to 1.24). There was little evidence to suggest other targets affect the outcomes.

Conclusions and relevance

ARDB1 antagonism may be a promising repurposing candidate for VaD. Pharmacovigilance studies are required to further examine ACE inhibitors’ potential to increase VaD risk. There is little evidence to support repurposing of many licensed lipid-lowering, antihypertensive and anti-inflammatory drugs for VaD prevention or treatment.

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