Association of Baseline Metabolomic Profiles With Incident Stroke and Dementia and With Imaging Markers of Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease is a major cause of stroke and dementia. Metabolomics can help identify novel risk factors to better understand pathogenesis and predict disease progression and severity. METHODS: We analyzed baseline metabolomic profiles from 118,021 UK Biobank participants. We examined cross-sectional associations of 325 metabolites with MRI markers of small vessel disease, evaluated longitudinal associations with incident stroke and dementia, and ascertained causal relationships using Mendelian randomization. RESULTS: In cross-sectional analyses, lower levels of apolipoproteins, free cholesterol, cholesteryl esters, fatty acids, lipoprotein particle concentrations, phospholipids, and triglycerides were associated with increased white matter microstructural damage on diffusion tensor MRI. In longitudinal analyses, lipoprotein subclasses of very large high-density lipoprotein cholesterol (HDL) were associated with an increased risk of stroke, and acetate and 3-hydroxybutyrate were associated with an increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many findings. A few metabolites had consistent associations across multiple analysis types. Increased total lipids in very large HDL and increased HDL particle size were associated with increased white matter damage (lower fractional anisotropy: OR: 1.44, 95% CI 1.07–1.95, and OR: 1.19, 95% CI 1.06–1.34, respectively; mean diffusivity: OR: 1.49, 95% CI 1.11–2.01, and OR: 1.24, 95% CI 1.11–1.40, respectively) and an increased risk of incident all stroke (HR: 4.04, 95% CI 2.13–7.64, and HR: 1.54, 95% CI 1.20–1.98, respectively) and ischemic stroke (HR: 3.12, 95% CI 1.53–6.38; HR: 1.37, 95% CI 1.04–1.81). Valine was associated with decreased mean diffusivity (OR: 0.51, 95% CI 0.30–0.88) and had a protective association with all-cause dementia (HR: 0.008, 95% CI 0.002–0.035). Increased levels of cholesterol in small HDL were associated with a decreased risk of incident all stroke (HR: 0.17, 95% CI 0.08–0.39) and ischemic stroke (HR: 0.19, 95% CI 0.08–0.46) and were supported by evidence of a causal association with MRI-confirmed lacunar stroke (OR: 0.96, 95% CI 0.93–0.99). DISCUSSION: In this large-scale metabolomics study, we found multiple metabolites associated with stroke, dementia, and MRI markers of small vessel disease. Further studies may help inform the development of personalized prediction models and provide insights into mechanistic pathways and future treatment approaches.