A new study shows a strong link between altered liver function and the development of Alzheimer’s disease (AD). This correlates with recent data on the role played by diseases affecting the systemic metabolism, such as diabetes and high blood cholesterol, in disruptions of brain function as in AD.
The study looked at over 1,500 individuals who took part in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The researchers examined the levels of five liver enzymes which reflect the function of the liver, namely, total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).
The focus was on detecting any association between these values and the presence of cognitive impairment, biomarkers of AD, brain glucose metabolism as shown by PET scans, brain atrophy seen on MRI scans, and the accumulation of the hallmark protein amyloid-β in the brain.
Alzheimer's disease: the amyloid-beta peptide accumulates to amyloid fibrils that build up dense amyloid plaques. 3d rendering - Image Credit: Juan Gaertner / Shutterstock
The researchers found that individuals with disturbed liver metabolism were positive for three significant outcomes: a higher risk of cognitive impairment, increased cerebrospinal (CSF) concentrations of the proteins found in Alzheimer’s disease, such as amyloid-β and phosphorylated tau protein, and lower levels of glucose metabolism in the brain as shown by PET imaging.
The liver is a key organ in the body’s metabolism, producing a host of vital molecules and detoxifying multiple chemicals, as well as handling the load of diverse and abundant metabolites from the gut. A significant failure in the function of this important organ plays a role in elevating the risk of AD.
In particular, higher AST:ALT ratios as well as lower ALT levels were both significantly associated with a diagnosis of AD. An increased AST:ALT ratio increased the risk of AD by almost 8 times, while a low ALT increased it by 87%.
ALT is reduced with age and could be one reason for the increased incidence of AD with advancing age. Alterations in liver enzymes result in abnormalities in several metabolites produced by the liver, a finding already known to be present in AD.
Another possible result is a disrupted energy metabolism due to low ALT and high AST:ALT levels. These enzymes play a crucial role in the generation of glucose in the liver as well as of neurotransmitters like glutamate which are needed to maintain normal brain connections. This may explain the reduced glucose metabolism in the brain, particularly in those areas that are responsible for executive function and memory. A low glucose turnover in the brain is well known to be an early sign of impending or developing AD.
The two-year international study covered 60 sites, in collaboration with the Alzheimer's Disease Metabolomics Consortium (ADMC), in an advanced attempt to unveil the real issues underlying the development of AD. Researcher Andrew J. Saykin explains, “It represents the new wave of Alzheimer's research, employing a broader systems approach that integrates central and peripheral biology. No stone can be left unturned in our attempt to understand the disease and to identify viable therapeutic targets.”
The current research was funded by the National Institute of Aging (NIA) as part of its thrust to better understanding and treatment of AD, called the Accelerating Medicine Partnership for Alzheimer's Disease. Whereas earlier work looked mainly at the brain, the new way of thinking about AD embraces the whole system, in what is popularly called the “gut-brain-liver” pathway. This will help scientists examine brain function but also pick up other bits of the puzzle to better recognize what is going wrong with the body and how these mixed signals are disrupting brain function.
ADMC leader Rima Kaddurah-Daouk elaborated on this: “We now have to study the brain as an organ that is communicating with and connected to other organs that support its function and that can contribute to its dysfunction. The concept emerges that Alzheimer's disease might be a systemic disease that affects several organs including the liver.”
The evidence of systemic metabolic disruption in AD can help evolve tests to detect the condition earlier and improve treatment, as well as direct personalization of therapy. The reason is that understanding how each patient shows the effects of numerous interactions between the personal lifestyle choices, environment and genetic make-up will help deliver precision medical care as opposed to a one-size-fits-all approach. In fact, the current study will already help healthcare providers to decide on evaluating patients who show evidence of liver dysfunction for early signs of AD as well.
The study titled, 'Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers', is published in Jama Network Open.
Nho K, Kueider-Paisley A, Ahmad S, et al. Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers. JAMA Netw Open. Published online July 31, 20192(7):e197978. doi:10.1001/jamanetworkopen.2019.7978, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2740062