Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide. With limited treatment options available to slow its progression, recent advancements in understanding the disease’s pathology have brought hope for new therapeutic approaches.
A breakthrough discovery demonstrates that the liver plays a crucial role in clearing amyloid-beta (Aβ), the protein associated with AD, from the blood, and that enhancing liver function could be a promising therapeutic strategy. The findings were published in the journal Acta Neuropathologica.
AD is traditionally considered a disease of the brain, but research has shown that the pools of Aβ in the brain and the periphery communicate with each other. Approximately 40%–60% of brain-derived Aβ is cleared through transport into the periphery via the blood-brain barrier and other pathways. However, where and how brain-derived Aβ peptides are cleared in the periphery remained unclear until recently.
Researchers found that about 13.9% of Aβ42 and 8.9% of Aβ40 were removed from the blood when flowing through the liver. This capacity was found to decrease with age, as Aβ receptor LRP-1 expression was down-regulated in hepatocytes in aged animals. Partial blockage of hepatic blood flow increased Aβ levels in both blood and brain interstitial fluid. When enhancing hepatic Aβ clearance via LRP-1 overexpression, researchers observed a reduction in cerebral Aβ deposition and cognitive impairments in APP/PS1 mice, a mouse model of AD.
These findings demonstrate that the liver plays a critical role in clearing Aβ from the blood and regulating brain Aβ levels. The capacity of the liver to clear Aβ declines with age, which could be a factor in AD development. This research suggests that enhancing hepatic Aβ clearance could be a novel therapeutic approach for AD.
The relationship between impaired hepatic function and cognitive impairment has been established in previous studies. Researchers have provided experimental evidence showing that the chronic decline of Aβ clearance in the liver increases brain Aβ deposition and aggravates tau hyperphosphorylation, neuroinflammation, neurodegeneration, and cognitive deficits in APP/PS1 mice.
The liver’s role in clearing Aβ from the blood has implications for both the diagnosis and treatment of AD. Chronic hepatic disorders or diseases may lead to increased Aβ levels, potentially resulting in incorrect or missed diagnosis of AD based on biomarkers. Future biomarker studies on AD diagnosis involving blood Aβ should take into account the effects of chronic hepatic disorders or diseases.
This research supports the peripheral sink hypothesis, which postulates that central and peripheral pools of Aβ coexist in equilibrium and that sequestering Aβ in the blood could facilitate the efflux of Aβ from the brain. The findings suggest that targeting the periphery, including the liver, may be a promising therapeutic approach for AD. Most importantly, targeting the periphery for Aβ clearance may avoid adverse effects of therapeutics on the brain through the blood-brain barrier.
