Abstract
BACKGROUND: Emerging evidence suggests complex interaction between bilirubin, a heme catabolism byproduct, and neurodegenerative disorders (NDDs), though existing studies report inconsistent associations. We aimed to investigate longitudinal relationship between serum bilirubin levels and NDD risk in a large population-based cohort.
METHODS: Utilizing data from the UK Biobank, we investigated the association between baseline direct bilirubin (DBIL) and total bilirubin (TBIL) and the risk of common NDDs using Cox proportional hazards regression analysis. We further performed interaction and subgroup analysis for the identified significant association.
RESULTS: Elevated serum DBIL level at baseline was associated with a higher risk of incident Parkinson’s disease (PD) (HR = 1.12, P = 7.87E-05, 95 % CI = 1.06-1.19) and Alzheimer’s disease (AD) (HR = 1.09, P = 0.002, 95 % CI = 1.03-1.15). Interaction analysis revealed specific effects of age regarding the association between DBIL and PD. Specifically, higher serum DBIL served as a greater risk factor in participants with older ages. In addition, nominal association was identified between TBIL level and risk of PD (HR = 1.01, P = 0.02, 95 % CI = 1.00-1.02).
CONCLUSIONS: Our study demonstrates subtype-specific association between bilirubin and neurodegeneration, with DBIL showing particular relevance for PD and AD risk. These findings position DBIL as a potential biomarker and highlight the need for mechanistic studies on bilirubin’s dual roles in neurodegeneration.