Deciphering the role of liver metabolic enzymes in dementia pathogenesis

The relationship between liver metabolic enzymes and the risk of dementia, as well as whether genetic factors can explain these potential associations, remains unclear. Based on data from 347,605 dementia-free British adults in the UK Biobank, we categorized participants into normal and abnormal liver metabolic enzymes groups according to serum liver metabolic enzyme levels and assessed the longitudinal risk of incident dementia and changes in brain structure across these groups. Subsequently, we employed a two-sample Mendelian randomization (MR) analysis to explore the influence of genetic factors and further investigated the potential role of confounding factors such as lifestyle. The results showed that abnormal liver metabolic enzymes were associated with a higher risk of dementia. However, MR analysis did not reveal a statistically significant association between liver metabolic enzymes and dementia, indicating that genetic factors may not primarily drive the association. Additionally, abnormal liver metabolic enzymes were associated with reduced gray matter (GM) volume, indicating that changes in GM volume may be a potential mechanism through which abnormal liver metabolic enzymes influences dementia risk. In summary, this study indicates that individuals with abnormal liver metabolic enzymes have a higher risk of dementia, and genetic susceptibility does not explain the observed higher risk of dementia among participants with abnormal liver metabolic enzymes. • Abnormal liver function was associated with a higher risk of dementia. • Genetic susceptibility did not explain the observed higher risk of dementia. • People with abnormal liver function benefited more from healthy lifestyle.