A link between liver dysfunction and Alzheimer’s disease has been discovered


New research from the Alzheimer’s Disease Metabolomics Consortium (ADMC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) has uncovered novel connections between liver dysfunction and Alzheimer’s disease (AD), paving a new path toward a systems-level view of Alzheimer’s relevant for early detection and ultimately for prevention.

The study, published today in JAMA Network Open, was led by IU School of Medicine radiology professor Kwangsik Nho, Ph.D. and explores the relationship between blood-based biochemical markers of liver function and established Alzheimer’s disease biomarkers including multi-modal neuroimaging.

With increasing evidence linking Alzheimer’s disease to diabetes or high cholesterol and other systemic illnesses, Nho and colleagues discovered an association between liver function and Alzheimer’s, which adds to the understanding of metabolic dysfunction in the disease.

Researchers evaluated more than 1,500 participants from the National Institute of Aging (NIA)-sponsored ADNI over two years using five serum-based liver function assays, which measure enzymes predominantly found in the liver.

By using the peripheral biochemical markers, the team was able to uncover evidence of metabolic disturbance and gain a new perspective on altered liver enzymes association with both cognitive impairment and AD pathophysiology including amyloid-β and phosphorylated tau in cerebrospinal fluid (CSF) and reduced brain glucose metabolism on PET scans.

“This study was a combined effort of the ADNI, a 60-site study, and the ADMC. It represents the new wave of Alzheimer’s research, employing a broader systems approach that integrates central and peripheral biology,” said Andrew J. Saykin, PsyD, director of the Indiana Alzheimer Disease Center at IU School of Medicine and site principal investigator for the Alzheimer’s Disease Metabolomics Consortium.

“In this study, blood biomarkers reflecting liver function were related to brain imaging and CSF markers associated with Alzheimer’s,” Saykin said. “No stone can be left unturned in our attempt to understand the disease and to identify viable therapeutic targets.”

Funded by the NIA under its Accelerating Medicine Partnership for Alzheimer’s Disease program, this research is a result of international collaboration, led by Rima Kaddurah-Daouk, Ph.D., of Duke University, that attempts to connect the dots in the body’s “gut-liver-brain” communication pathway and relate this to AD.

“This is a new paradigm for Alzheimer’s research,” Nho said. “Until now, we only focused on the brain.

Our research shows that by using blood biomarkers, we can still focus on the brain but also find evidence of Alzheimer’s and improve our understanding of the body’s internal signaling.”

“While we have focused for too long on studying the brain in isolation, 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,” said Kaddurah-Daouk.

The study’s focus outside the brain aligns with known risk factors for Alzheimer’s disease, including metabolic disorders.

According to Nho, looking elsewhere in the body for signals correlated with the disease can provide important clues toward detection and ultimately prevention.

By using the peripheral biochemical markers, the team was able to uncover evidence of metabolic disturbance and gain a new perspective on altered liver enzymes association with both cognitive impairment and AD pathophysiology including amyloid-β and phosphorylated tau in cerebrospinal fluid (CSF) and reduced brain glucose metabolism on PET scans.

Not only does this research shed light on the connection between the liver and brain, but this line of research is expected to ultimately enable physicians to provide more personalized patient care.

Through IU’s Grand Challenge Precision Health Initiative and the ADMC precision medicine approach, researchers and physicians can focus on how a patient’s environment, genes and lifestyle impact their overall health.

Instead of a one-size-fits-all tactic, precision medicine allows researchers and physicians to more accurately predict and prevent devastating diseases, like Alzheimer’s.

The NIA-ADMC research program opens the door for physicians treating patients with liver dysfunction to ensure they aren’t also exhibiting early-stage Alzheimer’s disease.

The Alzheimer Disease Metabolomics Consortium (ADMC) led by Dr. Kaddurah-Daouk is a bold initiative that brings together leaders in Alzheimer’s disease clinical and basic research to work in close collaboration with centers of excellence in metabolomics, genetics, biochemistry, engineering and bioinformatics.

In addition to Duke and IU School of Medicine, other institutions included Helmholtz Zentrum München, Neuherberg, Germany, Erasmus Medical Centre, Rotterdam, the Netherlands, Rosa & Co LLC, San Carlos, California, University of Texas Health Science Center at San Antonio, San Antonio, University of Pennsylvania, Philadelphia and San Francisco Veterans Affairs Medical Centers, University of California-San Francisco and University of Oxford.

While we still do not know exactly what causes the development of Alzheimer’s disease, specialists have been hard at work trying to identify the most salient risk factors.

New research has now identified a new player when it comes to Alzheimer’s risk: the liver.

This week, at the yearly Alzheimer’s Association International Conference — held in Chicago, IL — researchers led by Dr. Mitchel A. Kling, an associate professor of psychiatry at the University of Pennsylvania in Philadelphia, have presented the intriguing findings of their latest study.

They observed that Alzheimer’s disease risk is associated with reduced levels of plasmalogens, a type of phospholipid produced in the liver. They play key roles in maintaining the health of brain cells.

From the liver, plasmalogens are carried to the brain and other organs through the blood. Levels of these phospholipids can be measured through specialized tests that have been devised by Dr. Kling in collaboration with colleagues from the Alzheimer’s Disease Metabolomics Consortium at Duke University in Durham, NC.

The researchers identified three indices — assessing the ratios of different plasmalogens to each other, the ratios of plasmalogens to other lipids, and a combination of these measurements — that allow them to determine the amount of plasmalogen as it relates to cognitive functioning.

Specifically, they were interested in confirming whether decreased plasmalogen levels were linked with an increased risk of developing various degrees of cognitive impairment, including: Alzheimer’s disease, mild cognitive impairment (MCI), or significant memory concerns (SMC).

Changes in the liver influence risk

Dr. Kling and team assessed the levels of several different plasmalogens, including ones containing specific omega-3 fatty acids: docosahexaenoic acid (DHA), and eicosapentaenoic acid.

They also measured the levels of one omega-6 fatty acid, and of some nonplasmalogen lipids closely related to plasmalogens.

The measurements were taken in samples of blood-based bodily fluids collected from two different groups of study participants.

he first group was made of 1,547 people diagnosed with Alzheimer’s disease, MCI, or SMC, as well as a number of people confirmed to be cognitively normal. These participants were enrolled in the Alzheimer’s Disease Neuroimaging Initiative.

The second group was made of 112 individuals with Alzheimer’s or MCI, or who were considered cognitively normal. These latter participants were recruited via the Penn Memory Center.

Dr. Kling and colleagues saw that lower values of the indices they measured corresponded to a higher risk of developing Alzheimer’s, and a similar association was observed for MCI diagnoses.

Moreover, the scientists also noticed that decreased levels of certain plasmalogens appeared to be linked with heightened levels of the tau protein, which is a hallmark of Alzheimer’s disease.

“This research shows that an age-related deficiency of plasmalogens could lead to an increased risk of Alzheimer’s disease, because the liver cannot make enough of them,” notes Dr. Kling.

“This research […] highlights a potential relationship between conditions such as obesity and diabetes and Alzheimer’s — as the liver has to work harder to break down fatty acids over time.”

“This could lead to the eventual destruction of the peroxisomes [functional elements within cells] that create plasmalogens which thus, increases the risk of Alzheimer’s.”

A ‘promising’ journey of discovery

These observations, the team adds, might also explain why Alzheimer’s patients who receive fish oil or supplementary DHA do not show any improvement of cognitive function.

This may happen because the liver is unable to integrate the fatty acids into the plasmalogens.

Another intriguing notion is the fact that certain genes thought to play a role in Alzheimer’s disease also regulate the transport and metabolism of lipids, so researchers are now interested in finding out whether this has any bearing on the relationship between lipid production and brain health.

“Our findings provide renewed hope for the creation of new treatment and prevention approaches for Alzheimer’s disease,” Dr. Kling explains. “Moving forward, we’re examining the connections between plasmalogens, other lipids, and cognition, in addition to gene expression in the liver and the brain.”

“While we’re in the early stages of discovering how the liver, lipids, and diet are related to Alzheimer’s disease and neurodegeneration, it’s been promising,” he adds.

Indiana University School of Medicine
Media Contacts: 
Katie Duffey – Indiana University School of Medicine
Image Source:
The image is in the public domain.

Original Research: Open access
“Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers”. Kwangsik Nho et al.
JAMA Network Open. doi:10.1001/jamanetworkopen.2019.7978


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