Indeed, most of the brain Aβ can be cleared via transportation to the periphery.
This fact prompted more investigators to focus on the development of peripheral Aβ clearance-based strategies, a safer therapy. Unfortunately, immunotherapy targeting the central clearance of Aβ shows limited efficacy, and several adverse effects have been reported in clinical trials, such as neuroinflammation, neuronal hyperactivity, and enhanced neurotoxicity linked to Aβ oligomerization. Therefore, strategies to scavenge Aβ from the brain are considered a priority in the treatment of AD. It is believed that the imbalance between Aβ production and clearance plays a pivotal role in AD pathogenesis. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. We further propose that compromised peripheral Aβ clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. Recently, the contribution of peripheral systems, particularly the liver, to Aβ clearance has sparked an increased interest. Historically, strategies targeting Aβ clearance have typically focused on central clearance, but with limited clinical success.
Imbalanced amyloid-beta (Aβ) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Alzheimer’s disease (AD), an age-related neurodegenerative disorder, is currently incurable.
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