Study Authors: Kwangsik Nho, Alexandra Kueider-Paisley, et al.
Target Audience and Goal Statement:
Gastroenterologists, neurologists, geriatricians, hepatologists, internists, primary care physicians, family physicians
The goal was to examine potential associations between liver dysfunction and the development of Alzheimer’s disease, measures of cognition, and results using neuroimaging and cerebrospinal fluid (CSF) biomarkers.
Questions Addressed:
- What is the role of metabolic dysfunction in Alzheimer’s disease (AD), with special attention to liver function?
- What liver function markers are associated with cognitive dysfunction and the amyloid, tau, and neurodegeneration (A/T/N) biomarkers for AD?
- What might be the reason/s underlying the associations found between serum liver function markers, imaging results, and cognitive dysfunction (including AD)?
Study Synopsis and Perspective:
Altered liver enzymes were consistently associated with cognitive changes and AD in a large observational study of older adults.
Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratios were significantly increased in people who had cognitive impairment and AD biomarkers for A/T/N compared with cognitively normal people, reported Andrew Saykin, PsyD, of the Indiana University School of Medicine in Indianapolis, and Rima Kaddurah-Daouk, PhD, of Duke University, and co-authors in JAMA Network Open.
Lower levels of ALT also were associated with poor cognitive performance and some markers of AD, and elevated alkaline phosphatase levels also were significantly associated with poor cognition.
The study “is the most comprehensive analysis to date linking blood biomarkers — in this case, clinical lab tests of liver function — with cognition, MRI measures of brain structure, and molecular tests of Alzheimer’s associated amyloid and tau proteins,” Saykin told MedPage Today.
“The significance of these associations is that they underscore the importance of connecting peripheral and central biological processes,” he said. “Now that we know they are related, new questions emerge: How do central and peripheral processes evolve over time? How do longitudinal changes in these blood analytes relate to clinical, cognitive, and neural changes? What are the causal directions and pathways? Most importantly, are there medications or lifestyle interventions that influence liver function that might reduce the risk of developing Alzheimer’s disease or related dementias?”
The study was conducted for the Alzheimer’s Disease Metabolomics Consortium(ADMC), part of the National Institute on Aging’s Accelerated Medicine Partnership for Alzheimer’s Disease. ADMC researchers are “trying to map global metabolic changes across the trajectory of the disease,” said Kaddurah-Daouk, who heads the consortium. “They are measuring thousands of chemicals in the blood to define when changes in metabolism happen and the mechanisms that lead to metabolic failures.”
In their analysis, the researchers looked at five serum-based liver function markers that had been measured from 2005 to 2013 in 1,581 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants: total bilirubin, albumin, alkaline phosphatase, ALT, and AST.
Primary outcomes included a diagnosis of AD, composite scores for executive functioning and memory, CSF levels of amyloid-β and tau, brain atrophy measured by MRI, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) PET, and amyloid-β accumulation measured by [18F] florbetapir PET.
Participants were an average age of 73, and 56% were men. The study population 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.
The researchers found that individuals with elevated AST:ALT ratios were more likely to have an AD diagnosis (OR 7.932, 95% CI 1.673-37.617; P=0.03) than cognitively normal adults were. Increased AST:ALT ratio was also linked to poor cognition, lower CSF levels of the 42-residue form of amyloid-β, increased amyloid-β deposition, higher CSF levels of phosphorylated tau and total tau, and reduced brain glucose metabolism.
In addition, levels of ALT were significantly decreased in AD patients compared with cognitively normal individuals (OR 0.133, 95% CI 0.042-0.422; P=0.004). Lower levels of ALT also were associated with increased amyloid-β deposition, reduced brain glucose metabolism, greater brain atrophy, and poor cognition.
In addition to changes in ALT levels and AST:ALT ratios, elevated alkaline phosphatase levels also were significantly associated with poor cognition.
“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, many other organs that support its function and that can contribute to its dysfunction,” Kaddurah-Daouk told MedPage Today. “Hence, the emerging concept that Alzheimer’s might be a systemic disease that affects several organs, including the liver, and that these changes in the body can lead to metabolic problems in the brain needs to be more fully explored.”
Diet, gut bacteria, lifestyle and environmental factors, and genes “all can contribute to failures in our metabolism,” she pointed out. “These failures can affect peripheral organs and also the brain.”
Study limitations, the researchers noted, included the observational design of ADNI, which limited the ability to make assumptions about causality, and the relationship between liver enzymes and AD still needs to be studied prospectively. In addition, the investigators did not adjust for alcohol consumption and used γ-glutamyltransferase as a surrogate, but that marker generally indicates long-term, not episodic, heavy drinking.
Key findings remained significant after adjusting for γ-glutamyltransferase and statin use, the team said. “However, given the associations with liver function measures and A/T/N biomarkers for Alzheimer’s disease, it appears that liver function may play a role in the pathogenesis of Alzheimer’s disease, but limitations should be taken into account before further extrapolating our findings … Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.”
Source reference: JAMA Network Open 2019: 2(7): e197978
Study Highlights: Explanation of Findings
The researchers explained that they conducted the study in the context of increasing evidence pointing to the role of liver function in the pathophysiology of 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,” the team wrote.
The cohort study, which tracked liver function in 1,581 older adults, found that elevated AST:ALT ratios were associated with AD diagnosis, poor cognition, lower CSF levels of amyloid-β 1-42, increased deposition of amyloid-β, higher CSF levels of phosphorylated tau and total tau, lower brain glucose metabolism, and greater brain atrophy.
“Consistent associations of serum-based liver function markers with Alzheimer disease biomarkers highlight the involvement of metabolic disturbances in the pathophysiology of Alzheimer disease,” the investigators said.
They explained that due to the study’s prospective cohort design, it is not possible to draw any conclusions regarding causation and liver dysfunction. ALT and AST levels, among other biomarkers, are also used to determine general liver injury, and are associated with cardiovascular as well as metabolic diseases, which are themselves risk factors for AD and cognitive decline. However, until this study, there have been only a few studies linking peripheral biomarkers of liver function to central biomarkers related to AD and structural brain atrophy, the team noted.
Specifically, some of their novel findings included the following:
- Higher ALT levels were significantly associated with reduced amyloid-β deposition in the bilateral parietal lobes
- Increased AST:ALT ratios were significantly associated with increased amyloid-β deposition in the bilateral parietal lobes and right temporal lobe
- Higher AST:ALT ratios were associated with higher CSF p-tau values, which showed consistent patterns in the associations of CSF amyloid-β 1-42 or p-tau levels and brain glucose metabolism
- Higher ALT levels were associated with increased glucose metabolism in a widespread pattern, especially in the bilateral frontal, parietal, and temporal lobes
- Higher AST:ALT ratios were significantly associated with reduced glucose metabolism in the bilateral frontal, parietal, and temporal lobes
- Higher ALT levels were significantly associated with larger cortical thickness in the bilateral temporal lobes, which showed consistent patterns in the associations of brain glucose metabolism
Discussing potential mechanisms whereby liver function enzymes affect cognition, the authors noted: “Disturbed energy metabolism is one of the processes that may explain the observed lower levels of ALT and increased enzyme ratio in individuals with AD and impaired cognition. This finding is concordant with our observation that increased AST to ALT ratio values and lower levels of ALT showed a significant association with reduced brain glucose metabolism, particularly in the orbitofrontal cortex and temporal lobes.”
Brain glucose hypometabolism is an early signal of AD and cognitive impairment; ALT and AST are key enzymes in the liver’s gluconeogenesis and production of neurotransmitters, including glutamate, needed in maintaining synapses, added Saykin, Kaddurah-Daouk, and colleagues. “The liver-brain biochemical axis of communication should be further evaluated in model systems and longitudinal studies to gain deeper knowledge of causal pathways.”
Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston
Primary Source
JAMA Network Open
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