TY - JOUR
T1 - Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers
AU - Nho, Kwangsik
AU - Kueider-Paisley, Alexandra
AU - Ahmad, Shahzad
AU - Mahmoudiandehkordi, Siamak
AU - Arnold, Matthias
AU - Risacher, Shannon L.
AU - Louie, Gregory
AU - Blach, Colette
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Kastenmüller, Gabi
AU - Trojanowski, John Q.
AU - Shaw, Leslie M.
AU - Weiner, Michael W.
AU - Doraiswamy, P. Murali
AU - Van Duijn, Cornelia
AU - Saykin, Andrew J.
AU - Kaddurah-Daouk, Rima
N1 - Funding Information:
Funding/Support: Funding for the ADMC (Alzheimer Disease Metabolomics Consortium, led by Dr Kaddurah-Daouk at Duke University) was provided by grant R01AG046171 from the NIA, a component of the Accelerated Medicines Partnership for AD (AMP-AD) Target Discovery and Preclinical Validation Project, and grant RF1 AG0151550 from the NIA, a component of the M2OVE-AD Consortium (Molecular Mechanisms of the Vascular Etiology of AD–Consortium). Data collection and sharing for this project was funded by ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (Department of Defense award W81XWH-12-2-0012). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Co, CereSpir Inc, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Co, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corp, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Co, and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The work of various consortium investigators are also supported by various NIA grants (U01AG024904-09S4, P50NS053488, R01AG19771, P30AG10133, P30AG10124, K01AG049050, and R03 AG054936), the National Library of Medicine (grants R01LM011360 and R01LM012535), and the National Institute of Biomedical Imaging and Bioengineering (grant R01EB022574). Additional support came from Helmholtz Zentrum, the Alzheimer’s Association, the Indiana Clinical and Translational Science Institute, and the Indiana University-IU Health Strategic Neuroscience Research Initiative.
Funding Information:
For the ADMC (Alzheimer Disease Metabolomics Consortium, led by Dr Kaddurah-Daouk at Duke University) was provided by grant R01AG046171 from the NIA, a component of the Accelerated Medicines Partnership for AD (AMP-AD) Target Discovery and Preclinical Validation Project, and grant RF1 AG0151550 from the NIA, a component of the M2OVE-AD Consortium (Molecular Mechanisms of the Vascular Etiology of ADConsortium). Data collection and sharing for this project was funded by ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (Department of Defense award W81XWH-12-2-0012). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimers Association, Alzheimers Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Co, CereSpir Inc, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Co, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corp, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Co, and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimers Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The work of various consortium investigators are also supported by various NIA grants (U01AG024904-09S4, P50NS053488, R01AG19771, P30AG10133, P30AG10124, K01AG049050, and R03 AG054936), the National Library of Medicine (grants R01LM011360 and R01LM012535), and the National Institute of Biomedical Imaging and Bioengineering (grant R01EB022574). Additional support came from Helmholtz Zentrum, the Alzheimers Association, the Indiana Clinical and Translational Science Institute, and the Indiana University-IU Health Strategic Neuroscience Research Initiative.
Publisher Copyright:
© 2019 Nho K et al. JAMA Network Open.
PY - 2019/7/31
Y1 - 2019/7/31
N2 - 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..
AB - 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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U2 - 10.1001/jamanetworkopen.2019.7978
DO - 10.1001/jamanetworkopen.2019.7978
M3 - Article
C2 - 31365104
AN - SCOPUS:85070836994
SN - 2574-3805
VL - 2
JO - JAMA network open
JF - JAMA network open
IS - 7
M1 - e197978
ER -