Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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    Original Investigation
    July 31, 2019

    Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers

    Author Affiliations
    • 1Center for Computational Biology and Bioinformatics, Indiana Alzheimer Disease Center, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis
    • 2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
    • 3Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands
    • 4Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    • 5Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
    • 6Rosa & Co LLC, San Carlos, California
    • 7University of Texas Health Science Center at San Antonio, San Antonio
    • 8German Center for Diabetes Research, Neuherberg, Germany
    • 9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia
    • 10Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco
    • 11Duke Institute of Brain Sciences, Duke University, Durham, North Carolina
    • 12Department of Medicine, Duke University, Durham, North Carolina
    • 13Nuffield Department of Population Health, Oxford University, Oxford, United Kingdom
    JAMA Netw Open. 2019;2(7):e197978. doi:10.1001/jamanetworkopen.2019.7978
    Key Points español 中文 (chinese)

    Question  Are liver function markers associated with cognition and the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for Alzheimer disease?

    Findings  In this cohort study of 1581 older adults, elevated aspartate aminotransferase to alanine aminotransferase ratios were associated with diagnosis of Alzheimer disease, poor cognition, lower cerebrospinal fluid levels of amyloid-β 1-42, increased amyloid-β deposition, higher cerebrospinal fluid levels of phosphorylated tau and total tau, and reduced brain glucose metabolism. Lower levels of alanine aminotransferase were associated with increased amyloid-β deposition, reduced brain glucose metabolism, greater brain atrophy, diagnosis of Alzheimer disease, and poor cognition.

    Meaning  Consistent associations of serum-based liver function markers with Alzheimer disease biomarkers highlight the involvement of metabolic disturbances in the pathophysiology of Alzheimer disease.


    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.