Genetic and Lifestyle Risks for Coronary Artery Disease and Long-Term Risk of Incident Dementia Subtypes

ABSTRACT Background Shared genetic and lifestyle risk factors may underlie the development of both coronary artery disease (CAD) and dementia. This study aimed to examine if an increased genetic risk for CAD is associated with long-term risk of developing all-cause, Alzheimer’s, or vascular dementia, and investigate whether the presence of healthy lifestyle behaviours in the mid-to-late life period may attenuate this risk. Methods A prospective cohort study of 365,782 participants free from dementia for at least 5 years post-baseline assessment was conducted within the UK Biobank study. Genetic risk was assessed using a genome-wide polygenic risk score (PRS) for CAD, and lifestyle risk using a modified version of the American Heart Association’s Life’s Essential 8 Lifestyle Risk Score (LRS). Primary outcomes were incident all-cause, Alzheimer’s, and vascular dementia diagnoses obtained from linked electronic health records. Secondary outcomes were neuroimaging phenotypes with well-established links to future dementia risk measured in 32,592 participants recalled for MRI imaging. Results 8,870 cases of all-cause dementia were observed over a median 13.9-year follow-up. Higher genetic risk for CAD was associated with an elevated risk of all dementia subtypes (HRs = 1.08-1.16; p<0.001 for all). A higher LRS was associated with a modestly increased risk of all-cause dementia (HR = 1.06 [1.04-1.08]; p < 0.001), with this risk likely arising through increased rates of vascular dementia (HR = 1.22 [1.17-1.28]) as no evidence was found for any associations with Alzheimer’s disease (HR = 0.99 [0.95-1.02]; p = 0.535). Individuals with a combination of high genetic and high lifestyle risk scores for CAD were more than twice as likely to develop vascular dementia during long-term follow-up compared to those with low levels of both. This risk was substantially attenuated in those following healthy lifestyle behaviours at baseline, however, regardless of underlying genetic risk (e.g. HR for low vs high lifestyle risk scores = 1.43 [1.12-1.81] vs. 2.16 [1.73-2.69] respectively in individuals with high genetic risk). In a subset of individuals recalled for neuroimaging assessments, those with high genetic and lifestyle risk for CAD demonstrated a 30% greater volume of white matter hyperintensities than those with low risk, while showing little difference in grey matter or hippocampal volumes. Conclusions Individuals who are genetically predisposed to developing CAD also face an increased risk of developing dementia in old age. This risk is reduced in those adopting healthy lifestyle behaviours earlier in the lifespan, however, particularly in those at risk from dementia caused by underlying vascular pathology.