Causes and consequences of vascular dementia across the life course: Evidence from a UK Biobank phenome-wide and Mendelian randomization study

Abstract

BackgroundVascular dementia (VaD) is the second most common cause of dementia, yet its risk factors and biological mechanisms remain poorly understood. ObjectiveTo identify causes and consequences of VaD by developing a polygenic risk score (PRS) for VaD and conducting a phenome-wide association study (PheWAS), followed by Mendelian randomization (MR) analyses using data from the UK Biobank. MethodsUsing data from 334,758 UK Biobank participants, we first constructed a VaD PRS based on the most recent genome-wide association study (GWAS). We then performed an age-stratified PheWAS (39-53, 53-62, 62-72 years), examining 9,319 phenotypes associated with the VaD PRS. We followed up PheWAS hits with two-sample MR to evaluate causal relationships with VaD risk. ResultsOur PheWAS revealed age-dependent associations, with many relationships strengthening as age increased. Associations were found with vascular and Alzheimers dementias; cerebrovascular traits such as white matter hyperintensities (WMH), stroke, and intracerebral haemorrhage; adverse lipid profiles; elevated systolic blood pressure and glucose levels; reduced brain volumes (subcortical and hippocampal); and poorer cognitive function. The VaD PRS was also associated with higher risk of depression, Parkinsons disease, neuroinflammatory disorders, and decreased basal metabolic rate and fat-free mass. MR analyses supported causal effects for WMH (OR: 1.83, 95% CI: 1.39-2.40), depression (1.25, 1.02-1.54), lipid traits (e.g., apolipoprotein B/A1 ratio: 1.31, 1.06-1.62), HbA1c (1.14, 1.02-1.28), and diastolic (1.03, 1.01-1.04) and systolic (1.01, 1.01-1.02) blood pressure. Protective factors included years of schooling (0.76, 0.64-0.90), apolipoprotein A (0.74, 0.59-0.92), fat-free mass (0.84, 0.71-0.99), and basal metabolic rate (0.82, 0.69-0.97). ConclusionsOur findings highlight the central role of cardiometabolic and educational factors in the development of vascular dementia. Several modifiable risk factors--particularly blood pressure, glucose regulation, lipid levels, and years of schooling--showed evidence of causal effects on VaD risk. Age-stratified results suggest that early intervention, ideally from midlife, may offer the greatest preventive benefit by mitigating the progressive accumulation of vascular damage contributing to dementia risk.