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Background Albumin (ALB), globulin (GLB) and albumin-to-globulin ratio (AGR) are linked to vascular diseases, but their relationships with cerebral small vessel disease (CSVD) remain inadequately explored. This study aimed to examine the associations between these biomarkers and CSVD burden.Methods Participants from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were included. CSVD severity was assessed using total and modified CSVD burden scores derived from white matter hyperintensity (WMH), enlarged perivascular spaces in basal ganglia (BG-EPVS), lacunes and cerebral microbleeds. Logistic regression and two-sample Mendelian randomisation (MR) were employed to estimate associations and potential causal effects.Results Among 3042 subjects (mean age 61.2 years), lower ALB, higher GLB and lower AGR were significantly associated with greater total and modified CSVD burden after adjusting for confounders. Specifically, the risk of total CSVD burden was significantly increased for the lowest ALB tertile (cOR 1.31, 95% CI 1.07 to 1.60), highest GLB tertile (cOR 1.33, 95% CI 1.09 to 1.63) and lowest AGR tertile (cOR 1.46, 95% CI 1.19 to 1.79) compared with their respective reference tertiles. Similar patterns were observed for WMH and BG-EPVS. MR analysis revealed that genetically predicted ALB was inversely associated with WMH volume (β −0.07, 95% CI −0.13 to −0.01), while genetically predicted GLB was positively associated with WMH volume (β 0.05, 95% CI 0.01 to 0.10).Conclusions Lower ALB, higher GLB and lower AGR are associated with increased CSVD burden. Genetic evidence supports the causal roles of ALB and GLB in WMH development.