Association of multisystem vascular-related disease with incident parkinsonism: insights from a cohort study

Systemic vascular dysfunction has been implicated in parkinsonism, but prospective evidence on the cumulative burden of multisystem vascular-related disease (MVRD) and its relation to genetic susceptibility remains limited. We included 456,862 UK Biobank participants of White ethnicity with available genetic data who were free of diagnosed parkinsonism at baseline. MVRD comprised ischemic heart disease, stroke, chronic kidney disease, retinopathy, and neuropathy. Incident parkinsonism, excluding vascular parkinsonism, was ascertained during follow-up. Fine–Gray competing-risk models were used to estimate subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs), with all-cause mortality treated as the competing event. During a median follow-up of 11.8 years, 2559 incident parkinsonism cases occurred. Any MVRD was associated with a higher risk of parkinsonism (sHR 1.35; 95% CI 1.23, 1.48), and each additional MVRD-related condition was associated with a higher risk (sHR 1.30; 95% CI 1.21, 1.40). The associations increased with the number of MVRD-related conditions, with sHRs of 1.29, 1.73, and 2.52 for one, two, and three or more conditions, respectively, compared with none. The association between MVRD and parkinsonism was observed in both low- and high-genetic-risk groups, with no evidence of interaction. Results remained broadly consistent after excluding cases diagnosed during the first 10 years of follow-up. These findings suggest a graded association between MVRD burden and incident parkinsonism, adding to the evidence linking vascular health to neurodegeneration.