Abstract 14266: Is the Association Between Coronary Artery Disease and Adverse Brain Health Causal? A Combined Observational and Mendelian Randomisation Study

Introduction: Although coronary artery disease (CAD) is associated with worse brain health in observational studies, whether this is causal remains elusive.

Aim: To examine observational associations between CAD and brain health, and use Mendelian randomisation (MR) to test for causal relationships.

Methods: 472,120 UK Biobank participants were included. Outcomes were divided into brain morphology (white matter hyperintensity volumes [WMHVs] and hippocampal volumes [HVs]) and cognitive outcomes (reaction times [RTs] and visual memory [VM]). Generalized linear models were employed to explore the association between CAD and these brain health outcomes after adjusting for demographics, cardiometabolic risk factors and medications. To determine whether the observed associations were causal, we fitted MR inverse-variance weighted models, alongside sensitivity analyses for horizontal pleiotropy.

Results: Observational analyses showed that CAD participants had 1.8% (95% confidence interval [CI] =[1.5, 2.0]) longer (worse) RTs but this was attenuated to 1% after adjusting for antihypertensives, diabetes or lipid-lowering drugs; 15.9% [7.0, 25.8] greater WMHVs but this was attenuated to the null after controlling for cardiometabolic risk factors; and 1.7% [1.0, 2.5] lower HVs (1% after adjusting for antihypertensives). There was no association between CAD and VM. MR analyses showed that individuals with greater CAD genetic liability made 1.01% [1.00, 1.01] more errors on VM tests but there was no evidence of causal associations with RTs, WMHVs and HVs.

Conclusion: Observational analyses showed that CAD was associated with worse brain health, and addressing cardiometabolic risk factors was beneficial. However, MR analyses suggested a causal association only between genetic liability to CAD and worse VM. Future research should explore non-cardiometabolic factors (e.g., glutamate toxicity) to reduce cognitive impairment risk in individuals with CAD.