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Cited by 227Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

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

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Nho, Kwangsik, Kueider-Paisley, Alexandra, Ahmad, Shahzad, MahmoudianDehkordi, Siamak, Arnold, Matthias, Risacher, Shannon L., Louie, Gregory, Blach, Colette +11 more·2019·JAMA Network Open
DOI 10.1001/jamanetworkopen.2019.7978PMC PMC6669786
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Abstract

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.

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  • Evidence has pointed to the liver as a target organ in Alzheimer's due to its role in regulating metabolism and supporting the immune system.

    “Evidence has pointed to the liver as a target organ in Alzheimer’s due to its role in regulating metabolism and supporting the immune system [54–56]”

    From Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients (2024) · cites this paper as [56]

    The Introduction (page unavailable) links the liver’s metabolic activity to Alzheimer’s disease and says the evidence highlights the liver’s importance in AD pathophysiology. The Conclusions (page unavailable) also report associations between liver-function markers and AD biomarkers. Neither passage establishes the claimed role of the liver in supporting the immune system as a reason to regard it as a target organ in AD. (LLM, conf=0.85)

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Nho, K., Kueider-Paisley, A., Ahmad, S., MahmoudianDehkordi, S., Arnold, M., Risacher, S. L., Louie, G., Blach, C., Baillie, R., Han, X., Kastenmüller, G., Trojanowski, J. Q., Shaw, L. M., Weiner, M. W., Doraiswamy, P. M., van Duijn, C., Saykin, A. J., Kaddurah-Daouk, R., & for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
Affiliations
  • Indiana University Indianapolis (US)
  • Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
  • Erasmus MC (NL)
  • Duke University (US)
  • Rosa (United States) (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Helmholtz Munich (DE)
  • University of Pennsylvania (US)
  • San Francisco VA Medical Center (US)
  • Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands
Corresponding author
  • Saykin, Andrew J.
  • Kaddurah-Daouk, Rima
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2019-07-31
Volume
2
Issue
7
Pages
e197978
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2019.7978
PMC
PMC6669786
OpenAlex
W2966029669
Cited by
227
References
10
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2026: 24 · 2025: 31 · 2024: 43 · 2023: 38 · 2022: 44 · 2021: 26 · 2020: 21
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17.75
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Language
en
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cc-by
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Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, R01LM012535, U01AG024904, AG024904)
  • Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Brigham and Women's Hospital
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • Brown University
  • University of Pennsylvania
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Northwestern University
  • Washington University in St. Louis
  • Yeshiva University
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • University of Washington
  • Johns Hopkins University
  • University of Pittsburgh
  • University of Rochester
  • Rush University
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • York University
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, AG024904)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • University of California, Los Angeles
  • Albert Einstein College of Medicine, Yeshiva University
  • University of California, San Diego
  • University of California, Irvine
  • Medical Center, University of Rochester
  • Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
  • National Institute on Aging (U01-AG-024904, P30AG010133, W81XWH-12-2–0012, K01AG049050, AG 024904, RF1 AG0151550, U01AG024904-09S4, P30AG010124, RF1AG051550, R01AG019771, R01AG046171, R03AG054936)
  • National Institute of Mental Health (U01 AG024904, W81XWH-12-2-0012)
  • National Institute of Neurological Disorders and Stroke (P50NS053488)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, R01EB022574, U01 AG024904, AG024904)
  • U.S. National Library of Medicine (R01LM011360, R01LM012535)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
Keywords
Alzheimer's disease, liver function markers, liver enzymes, aspartate aminotransferase to alanine aminotransferase ratio, alanine aminotransferase, cerebrospinal fluid biomarkers, amyloid-beta, tau protein, neurodegeneration, brain atrophy, brain glucose metabolism, cognitive impairment, metabolic dysfunction, older adults
MeSH terms
Aged, Alanine Transaminase, Alkaline Phosphatase, Alzheimer Disease, Aspartate Aminotransferases, Bilirubin, Cognition, Female, Humans, Liver Function Tests, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Serum Albumin, Reproducibility of Results, Cohort Studies, Biomarkers, Fluorodeoxyglucose F18, Positron-Emission Tomography, Neuroimaging, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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