Altered liver enzymes consistently were tied to Alzheimer's disease, an observational study of older adults showed.
Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratios were significantly increased in people who had cognitive impairment and Alzheimer's disease biomarkers for amyloid, tau, and neurodegeneration (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 .
Lower levels of ALT also were associated with poor cognitive performance and some markers of Alzheimer's disease, they added.
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 said.
"The significance of these associations is that they underscore the importance of connecting peripheral and central biological processes," he told MedPage Today. "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?"
In this analysis, investigators looked at five serum-based liver function markers that had been measured from 2005 to 2013 in 1,581 (ADNI) participants: total bilirubin, albumin, alkaline phosphatase, ALT, and AST.
Primary outcomes included a diagnosis of Alzheimer's, 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 had an average age of 73 and 56% were men. The sample 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 Alzheimer's disease.
People with elevated AST to ALT ratios were more likely to have an Alzheimer's disease diagnosis (OR 7.932, 95% CI 1.673-37.617; P=0.03) than cognitively normal adults. 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.
Levels of ALT were significantly decreased in Alzheimer's disease patients compared with cognitively normal people (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.
Besides ALT levels and AST:ALT ratios, alkaline phosphatase elevations also were significantly associated with poor cognition.
The analysis was conducted for the (ADMC), part of the National Institute on Aging's . 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."
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."
"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."
This study had several limitations, the researchers noted. The observational design of ADNI limited the ability to make assumptions about causality, and the relationship between liver enzymes and Alzheimer's disease needs to be studied prospectively. 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. "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," the investigators wrote.
Disclosures
Funding for the Alzheimer Disease Metabolomics Consortium was provided by a grant from the NIA. Data collection and sharing for this project was funded by an ADNI NIH grant and Department of Defense ADNI award. ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering, and industry.
Saykin reported relationships with the NIH, Avid Radiopharmaceuticals, Eli Lilly, Siemens Healthcare, Arkley BioTek, and Springer-Nature publishing. Kaddurah-Daouk reported being an investor on key patents in the field of metabolomics, including applications for Alzheimer's disease. Co-authors disclosed multiple relevant relationships with industry.
Primary Source
JAMA Network Open
Nho K, et al "Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers" JAMA Network Open 2019; DOI: 10.1001/jamanetworkopen.2019.7978.