Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults

Abstract The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross‐sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow‐up were included from the UK Biobank; 5542 all‐cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; P FDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; P FDR = 0.010), AST to ALT ratio (HR, 1.195; P FDR <0.001), gamma‐glutamyl transpeptidase (GGT; HR, 1.066; P FDR <0.001), alcoholic liver disease (ALD; HR, 2.872; P FDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; P FDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U‐shaped association between Alb and AST and incident ACD ( P nonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver ( P FDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform ( P FDR <0.05). In sensitivity analysis, metabolic dysfunction‐associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.