When considering the organ systems of the body that most affect brain health and function, the liver is unlikely to be top of mind, but emerging evidence suggests that maybe it should be.
The brain is the most negatively impacted organ when the liver fails to perform its two primary functions of regulating metabolism and detoxification [1]. As one of the most energy intensive organs, using around 20% of the body’s energy, the brain depends on the liver to keep energy production in check. Anyone who has experienced the effects of alcohol intoxication, a state that occurs when alcohol is consumed faster than it can be metabolized, knows firsthand how the detoxifying capacity of the liver can impact brain function. Through the loss of these essential functions, liver disease can lead to cognitive impairment and promote neuropathological changes associated with increased dementia risk.
Liver disease generally progresses through four stages, from inflammation to fibrosis to cirrhosis, and ending in liver failure [2]. A study including over 170,000 veterans aged 65 and younger who had been diagnosed with dementia found that about 10% of them had liver biomarkers suggestive of advanced liver fibrosis, while 5% of them had biomarkers suggestive of liver cirrhosis [3]. The likelihood of liver fibrosis was assessed using a blood-based biomarker, the Fib4 score, which includes levels of two major liver enzymes (ALT and AST) along with platelet count. It should be noted that this test can be influenced by age, and may not be as reliable in those over age 65. Since the participants of this study did not have a history of cirrhosis, liver disease may not have been considered as a potentially reversible cause of their cognitive symptoms.
Liver dysfunction can lead to hepatic encephalopathy, a condition that induces a spectrum of neuropsychiatric symptoms, including confusion, altered sleep patterns, and personality changes [4]. These symptoms stem from the accumulation of toxic substances in the brain due to failed detoxification by the liver. These cognitive effects can often be reversed through treatments that reduce the burden of toxins.
This study highlights how liver dysfunction may be an underappreciated contributor to cognitive impairment in the general population. Non-alcoholic fatty liver disease (NAFLD), more recently called metabolic dysfunction-associated steatosis liver disease (MASLD), is becoming the most common chronic liver disease, with an estimated global prevalence around 30% [5]. Moreover, the vast majority of people with MASLD are unaware they have the condition [1]. It involves a range of metabolic disturbances stemming from the excessive accumulation of fat in the liver.
Imaging studies have shown that individuals with MASLD at midlife have reduced brain thickness and higher levels of damage in the brain vasculature in later life [6]. Many studies have also found MASLD to be associated with worse performance on cognitive tests and an increased risk for vascular dementia?, which may be related to these structural changes in the brain [1; 7].
Many risk factors associated with MASLD overlap with other metabolic or cardiovascular conditions, and it is likely that several of these factors contribute to dementia risk in a given individual. The mechanisms thought to be most involved are hyperammonemia, a condition where the body’s ammonia levels are elevated to a toxic level, and inflammation [1; 8].
Ammonia is a toxic waste product of protein metabolism [9]. It is normally converted to the non-toxic metabolite, urea, in the liver. If the liver isn’t working properly, ammonia can build up in the body and enter the brain. Ammonia is neurotoxic, even in small amounts, as it can negatively affect brain bioenergetics, activity, and fluid balance, resulting in brain swelling and seizures.
The excess accumulation of fat in the liver leads to changes in the level and composition of fat-derived molecules, such as fatty acids, in the blood [1; 8]. These fatty acids can go on to trigger chronic low-grade systemic inflammation and damage the blood-brain-barrier, allowing greater access of inflammatory cells and toxins, such as ammonia, into the brain. Inflammation-related damage is thought to be a primary mediator of the connection between liver dysfunction and vascular dementia [7].
The first step toward preventing liver-related cognitive impairment is awareness of your liver health status. Due to the high degree of underdiagnosis, many of us are not managing our metabolic liver disease simply because we don’t know we have it. Speak to your primary medical provider about checking your liver health through routine liver function blood tests that assess liver enzymes and proteins [10], and how best to manage liver-related risk through diet, exercise, and medication.
Betsy Mills, PhD, is a member of the ADDF's Aging and Alzheimer's Prevention program. She critically evaluates the scientific evidence regarding prospective therapies to promote brain health and/or prevent Alzheimer's disease, and contributes to CognitiveVitality.org. Dr. Mills came to the ADDF from the University of Michigan, where she served as the grant writing manager for a clinical laboratory specializing in neuroautoimmune diseases. She also completed a Postdoctoral fellowship at the University of Michigan, where she worked to uncover genes that could promote retina regeneration. She earned her doctorate in neuroscience at Johns Hopkins University School of Medicine, where she studied the role of glial cells in the optic nerve, and their contribution to neurodegeneration in glaucoma. She obtained her bachelor's degree in biology from the College of the Holy Cross. Dr. Mills has a strong passion for community outreach, and has served as program presenter with the Michigan Great Lakes Chapter of the Alzheimer's Association to promote dementia awareness.
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