Summary: Researchers have identified a connection between liver dysfunction and Alzheimer’s disease, offering new insight into how metabolic disturbances may contribute to neurodegeneration and suggesting potential routes for earlier detection and prevention.
Source: Indiana University School of Medicine
New collaborative research from the Alzheimer’s Disease Metabolomics Consortium (ADMC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) reveals novel links between liver function and Alzheimer’s disease (AD), supporting a systems-level view of AD that could improve early detection and prevention strategies.
The study, published in JAMA Network Open and led by Kwangsik Nho, Ph.D., professor of radiology at Indiana University School of Medicine, examined relationships between routine blood-based markers of liver function and established Alzheimer’s biomarkers, including multimodal neuroimaging and cerebrospinal fluid (CSF) measures. As evidence mounts connecting AD with metabolic conditions such as diabetes and hypercholesterolemia, this work highlights how peripheral metabolic health—particularly liver enzymes—may reflect or influence brain pathology.
Investigators analyzed data from more than 1,500 participants enrolled in the NIA-sponsored ADNI over a two-year period. They focused on five serum liver markers—total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST)—to detect metabolic disturbances. By integrating these peripheral biochemical markers with cognitive testing, CSF biomarkers, magnetic resonance imaging (MRI) measures of brain atrophy, and PET imaging of brain glucose metabolism and amyloid accumulation, the team identified consistent associations between altered liver enzymes, cognitive impairment, and core AD pathophysiology, including amyloid-β and phosphorylated tau.
Andrew J. Saykin, PsyD, director of the Indiana Alzheimer Disease Center and site principal investigator for the ADMC, emphasized the study’s integrated approach: “This research represents the next generation of AD studies by combining central and peripheral biology. Blood biomarkers that reflect liver function were linked with brain imaging and CSF markers tied to Alzheimer’s. To find effective therapeutics and improve diagnosis, we must examine all possible contributing systems.”
Funded by the National Institute on Aging through the Accelerating Medicines Partnership for Alzheimer’s Disease, the project was coordinated internationally under the leadership of Rima Kaddurah-Daouk, Ph.D., of Duke University. The investigators propose that a gut-liver-brain communication axis may play a meaningful role in AD development. “Traditionally we focused almost exclusively on the brain,” Nho noted. “Our findings show that blood-based liver markers can provide clues about brain pathology and help us better understand systemic signaling that may be relevant to Alzheimer’s.”
These results suggest practical implications for personalized medicine. By combining precision health approaches—considering genes, environment, and lifestyle—clinicians may better predict which patients are at higher risk for AD and tailor prevention or monitoring strategies accordingly. The ADMC’s precision medicine framework supports shifting away from a one-size-fits-all model toward individualized assessment, which could include monitoring liver function as part of comprehensive dementia risk evaluation. In clinical practice, identifying liver dysfunction might prompt additional cognitive screening or biomarker testing to detect early-stage AD.
The Alzheimer Disease Metabolomics Consortium, led by Dr. Kaddurah-Daouk, unites experts across clinical Alzheimer’s research, metabolomics, genetics, biochemistry, engineering, and bioinformatics. Along with Duke University and IU School of Medicine, participating institutions included research centers in Germany, the Netherlands, and several universities and medical centers across the United States, reflecting a collaborative, multidisciplinary effort to map systemic contributors to Alzheimer’s disease.
Source:
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
Abstract
Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers
Importance
Emerging evidence implicates liver function in Alzheimer’s disease pathophysiology. Because the liver is central to systemic metabolism, studying its relationship with cognition, neuroimaging findings, and CSF biomarkers can clarify how metabolic dysfunction contributes to AD.
Objective
To determine whether serum markers of liver function are associated with cognitive performance and the A/T/N biomarker framework for Alzheimer’s disease (amyloid, tau, and neurodegeneration).
Design, Setting, and Participants
This cohort study analyzed serum liver markers from September 2005 to August 2013 in 1,581 ADNI participants, alongside cognitive assessments, CSF biomarkers, brain atrophy measures, brain glucose metabolism by 18F-FDG PET, and amyloid-β accumulation by [18F]florbetapir PET. Associations were tested with generalized linear models adjusted for confounders and multiple comparisons; statistical analyses ran from November 2017 to February 2019.
Exposures
Five serum liver markers—total bilirubin, albumin, alkaline phosphatase, ALT, and AST—were evaluated as exposure variables.
Main Outcomes and Measures
Primary outcomes included AD diagnosis, composite scores for memory and executive function, CSF biomarkers, MRI-measured atrophy, brain glucose metabolism on FDG-PET, and amyloid burden on florbetapir PET.
Results
The cohort (n = 1,581; mean age 73.4 years) comprised cognitively normal participants and individuals across the spectrum from mild cognitive impairment to AD. Higher AST-to-ALT ratios and lower ALT levels were associated with an AD diagnosis and worse cognitive performance. Elevated AST/ALT ratios correlated with lower CSF amyloid-β1-42, greater amyloid deposition on PET, higher CSF phosphorylated tau and total tau, and reduced brain glucose metabolism. Lower ALT was also linked to greater amyloid deposition, reduced brain glucose metabolism, and increased atrophy.
Conclusions and Relevance
Consistent associations between serum liver function markers and cognitive measures and A/T/N biomarkers support a role for metabolic disturbances in AD pathophysiology. Whether these associations reflect causal mechanisms or secondary effects remains to be determined, but liver enzyme changes may offer new diagnostic and therapeutic opportunities for Alzheimer’s disease.