The liver as a metabolic and immune hub in Alzheimer’s disease: From mechanisms to therapeutic opportunities

Research on Alzheimer's disease (AD) has traditionally focused on the brain. However, emerging evidence indicates that the liver acts as a silent partner in neurodegeneration. As a core hub for metabolic and immune regulation, the liver communicates bidirectionally with the brain via the liver-brain axis, participating in the regulation of various neurophysiological processes, including neurotransmitter regulation, feeding behavior, and cognition. This review summarizes how liver-derived hepatokines, inflammatory mediators, and metabolic products modulate brain function. We highlight that liver dysfunction disrupts the expression of critical molecules-including fibroblast growth factor 21, insulin-like growth factor 1, lipopolysaccharide, and lipocalin-2-thereby driving AD progression by impairing pathological protein clearance, activating neuroinflammation, exacerbating insulin resistance and oxidative stress, and disrupting lipid metabolism. We also discuss the therapeutic potential of targeting the liver-brain axis through lifestyle interventions (e.g., exercise and diet) and pharmacological approaches, to identify novel strategies to delay AD progression. In summary, we underscore the pivotal role of the liver-brain axis in AD pathogenesis and propose it as a promising target for early diagnosis and innovative therapies.