The Liver-brain Axis: A Three-stage Model Linking MASLD to Cognitive Impairment and Dementia

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver condition affecting nearly 40% of the global population, and is increasingly recognized for its systemic impacts beyond hepatic complications. Emerging evidence has highlighted its role as an independent risk factor for cognitive impairment and dementia, particularly Alzheimer's disease, with significant bidirectional interactions mediated through the liver-brain axis. This review delineates a three-stage model, including systemic injury, cerebrovascular damage, and neurodegeneration, via which MASLD promotes cognitive impairment in conjunction with inflammation, oxidative stress, insulin resistance, lipotoxicity, gut-liver-brain axis dysregulation, and impaired ketogenesis. Additionally, we evaluate the emerging therapeutic strategies targeting metabolic dysfunction and neuroinflammation to mitigate the risk of dementia in patients with MASLD. By bridging critical gaps in the understanding of the liver-brain crosstalk, this study underscores the urgency of interdisciplinary research to address the growing burden of MASLD-related cognitive disorders and proposes translational avenues for early intervention and personalized care.