To investigate the association of liver function and liver disease with incident dementia risk, impaired cognition, and brain structural abnormalities.

Previous studies have proposed the close relationship between peripheral metabolism and brain metabolism may be associated with subsequent dementia onset. Therefore, the relationship between the liver, the most important peripheral metabolic organ, and dementia warrants further exploration.

Participants from the UK Biobank without baseline dementia were included. The longitudinal and cross-sectional associations were investigated 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; 5,542 all-cause dementia (ACD) 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/ALT (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),  fibrosis and cirrhosis of liver (HR, 2.285; P_FDR = 0.002), and metabolic dysfunction-associated steatotic liver disease (MASLD; HR, 2.862; P_FDR < 0.001), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified strong U-shaped associations between Alb and AST and incident ACD (P_non-linear < 0.05). Worse cognition was positively correlated with AST, AST/ALT, 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/ALT, ALD, and MASLD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (P_FDR < 0.05).

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.