Liver Fibrosis and the Risks of Impaired Cognition and Dementia: Mechanisms, Evidence, and Clinical Implications

Liver fibrosis, the progressive accumulation of scar tissue resulting from chronic liver disease, is increasingly recognized as a multi-system condition whose effects transcend the liver, affecting brain health. In parallel, dementia determining progressively impaired cognition severe enough to impede daily functioning, is a significant global health issue whose risk factors and pathogenic precursors are incompletely defined. Increasing evidence suggests that certain pathophysiological correlates of chronic liver disease may negatively affect neuronal health through incompletely defined pathophysiological mechanisms. With this background, we appraise our current understanding of the relationship between liver fibrosis and cognitive impairment/dementia, using a variety of different methodologies. Firstly, the pathophysiology and clinical significance of liver fibrosis are discussed. Next, we describe the various types of dementia and related risk factors. We then present research evidence supporting the association between cognitive impairment/dementia and liver fibrosis. We highlight both consistency and heterogeneity of findings, including the degree of association being affected by liver fibrosis severity. We thoroughly examine potential causal mechanisms, comprising the role of chronic systemic and neuroinflammation, insulin resistance, vascular dysfunction, and intestinal microbiota-liver-brain axis as potential connectors of liver health with cognitive impairment and dementia. We briefly analyze how sex and age may modify the above associations, how liver fibrosis and cognitive function should be diagnosed, and those potential preventive/treatment strategies based on the shared metabolic/inflammatory pathways associating liver fibrosis, cognitive impairment and dementia. Finally, major research gaps are identified, together with matching proposals for prioritizing advancements in our understanding of the increasingly identified connections between liver fibrosis and dementia/cognitive impairment.