Summary: A link between liver dysfunction and Alzheimer’s disease has been discovered. The findings add to the understanding of the role metabolic dysfunction plays in the neurodegenerative disease.
Source: Indiana University School of Medicine
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.
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.
Importance Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD.
Objective To examine whether liver function markers are associated with cognitive dysfunction and the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD.
Design, Setting, and Participants In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019.
Exposures Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables.
Main Outcomes and Measures Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography.
Results Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], −0.465 [0.180]; P = .02 for memory composite score; β [SE], −0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], −0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], −0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers). Conclusions and Relevance Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.