The Liver-Brain Axis and Peripheral Manifestations in Alzheimer’s Disease: Exploring New Perspectives


Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. It is characterized by progressive cognitive decline, memory loss, and behavioral changes.

The main pathological features of AD are the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain, as well as neuroinflammation and oxidative stress.

However, AD is not only a brain disease. Recent studies have suggested that other organs, such as the liver, may also be involved in the pathogenesis and progression of AD. The liver is a vital organ that performs many functions, such as metabolism, detoxification, and immune regulation. It also communicates with the brain through various pathways, forming the so-called liver-brain axis.

A team of researchers from the Universitat Autònoma de Barcelona (UAB) has investigated how the liver-brain axis is affected by AD in a mouse model of the disease. They used 3xTg-AD mice, which carry three genetic mutations that cause AD in humans, and compared them with non-transgenic (NTg) mice of the same age and sex. They focused on two aspects of the liver-brain axis: hepatic oxi-inflammation and neophobia.

Hepatic oxi-inflammation refers to the oxidative stress and inflammation that occur in the liver due to various factors, such as aging, diet, or infection. Oxidative stress is an imbalance between free radicals and antioxidants, which can damage cells and tissues. Inflammation is a defensive response to injury or infection, which can also cause tissue damage if excessive or chronic.


Alzheimer’s disease (AD) is the most prevalent form of dementia among older adults and is expected to increasingly affect the global population. Traditionally, research on AD has focused on brain alterations, particularly the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein.

However, emerging clinical evidence suggests the influence of peripheral organs on the pathophysiological development of the disease, including oxidative stress and inflammation theories of aging. This article delves into the novel concept of the liver-brain axis in AD and explores the broader spectrum of neuropsychiatric and behavioral manifestations associated with the disease.

Peripheral Involvement in AD

Recent studies have identified biomarkers of oxidative stress in the urine of AD patients and peripheral inflammation biomarkers that correlate with the risk of dementia. These findings suggest that AD not only affects the brain but also exerts physiological effects on peripheral tissues. Animal models have confirmed the existence of crosstalk between central and peripheral inflammation, highlighting the interconnectedness of these systems.

The Liver’s Role in AD

The liver, known for regulating metabolism and inflammation and supporting the immune system, has been implicated as a hotspot for oxidative stress. It also plays a role in the peripheral metabolism of Aβ. Liver dysfunction and impaired Aβ clearance have been suggested as early events in AD’s pathophysiology and are crucial in disease progression. Preliminary results from studies on 3xTg-AD mice, an established AD model, have indicated hepatic oxidative stress dysfunction at the disease’s onset. This has led to the emergence of the liver-brain axis as an area of focus in AD research.

Neuropsychiatric and Behavioral Manifestations

In addition to the classic cognitive impairments associated with AD, the disease is now recognized for its heterogeneous spectrum of neuropsychiatric and behavioral manifestations. Mouse models of AD, including the 3xTg-AD mice, have shown significant defects in memory and cognition, as well as a conspicuous neuropsychiatric phenotype. However, the relationship between these cognitive changes and peripheral abnormalities remains to be fully understood. Psychological stress and anxiety, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoid dysregulation have been identified as factors contributing to AD progression and the modulation of neuroimmune communication.

Extrinsic Factors and Premature Aging

Extrinsic environmental factors play a crucial role in maintaining neuroimmune-endocrine homeostasis and impact various physiological and psychological processes. Studies have demonstrated the effects of social isolation, stress, sex, menopause, and obesity on premature aging in both rodents and humans. Premature aging in animals is characterized by peripheral immunosenescence, oxidative and inflammatory stress, and nervous system derangement. Therefore, considering extrinsic factors such as housing conditions becomes important when studying the liver dysfunction and associated peripheral manifestations in AD.

Research Design and Conclusion

In this study, male and female 3xTg-AD mice were longitudinally studied, starting at 13 months and ending at 16 months, corresponding to advanced stages of the disease. The investigation aimed to assess liver dysfunction at different levels, including cellular oxi-inflammation, histological analysis, and functional correlates with the HPA axis and the liver-brain axis. The study also considered different housing conditions, including standard (grouped), naturalistic (natural death of congeners), and forced (experimental) social isolation.

In conclusion, AD research is expanding beyond the traditional focus on brain alterations, with increasing recognition of the liver-brain axis and the impact of peripheral organs on disease development. Understanding the broader spectrum of neuropsychiatric and behavioral manifestations

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