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. 2019 Jul 3;2(7):e197978.
doi: 10.1001/jamanetworkopen.2019.7978.

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

Kwangsik Nho  1 , Alexandra Kueider-Paisley  2 , Shahzad Ahmad  3 , Siamak MahmoudianDehkordi  2 , Matthias Arnold  2   4 , Shannon L Risacher  1 , Gregory Louie  2 , Colette Blach  5 , Rebecca Baillie  6 , Xianlin Han  7 , Gabi Kastenmüller  4   8 , John Q Trojanowski  9 , Leslie M Shaw  9 , Michael W Weiner  10 , P Murali Doraiswamy  2   11   12 , Cornelia van Duijn  3   13 , Andrew J Saykin  1 , Rima Kaddurah-Daouk  2   11   12 ; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
Affiliations

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

Kwangsik Nho et al. JAMA Netw Open. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Mr Louie reported receiving grants from the NIA during the conduct of the study. Dr Baillie reported receiving a salary from Rosa & Co outside the submitted work. Dr Kastenmüller reported receiving grants from NIH/NIA during the conduct of the study. Dr Trojanowski reported that he may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a coinventor; and receiving revenue from the sale of Avid to Eli Lily as a coinventor on imaging-related patents submitted by the University of Pennsylvania. Dr Shaw reported receiving research funding from the Michael J. Fox Foundation for PD Research; receiving grants from the National Institutes of Health/National Institute on Aging (NIH/NIA) during the conduct of the study; serving as a consultant for Eli Lilly, Novartis, and Roche; and providing quality control oversight for the Roche Elecsys immunoassay as part of responsibilities for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Dr Weiner reported having stock and stock options from Elan and Synarc; receiving travel expenses from Novartis, Tohoku University, Fundacio Ace, Travel eDreams, MCI Group, NSAS, Danone Trading, ANT Congress, NeuroVigil, CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego–ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer’s Disease, Pfizer, and AD PD meeting; receiving grants and personal fees from the NIH; receiving grants from the Department of Defense, Johnson & Johnson, GE, the Patient-Centered Outcomes Research Institute, California Department of Public Health, Vanderbilt University Medical Center, University of Missouri, Australian Catholic University, Hillblom Foundation, Alzheimer’s Association, Stroke Foundation, Veterans Administration, Siemens; and personal fees from Bioclinica, Cerecin/Accera, Genentech/Roche, Indiana University, Eli Lilly, Lynch Group GLC, Dolby Family Ventures, Nestec/Nestle, Health & Wellness Partners, Decision Resources LLC, Minds + Assembly, Japan Agency for Medical Research & Development, NYU Langone, Merck, Bionest Partners, and from Alzheon Inc outside the submitted work. Dr Doraiswamy reported receiving grants from the NIA and ADNI during the conduct of the study; receiving grants from the NIH, the Department of Defense, Lilly/Avid, Alzheimer’s Drug Discovery Foundation, the Karen L. Wrenn Trust, ASNR Foundation, Avanir; and Salix; serving on boards of Apollo Health and Baycrest; being a minor shareholder in Evidation Health, Turtle Shell, Advera Health Analytics, and Anthrotronix; receiving advisory fees from Cogniciti, Neuronix, NeuroPro, Anthrotronix, Verily, Apollo, Genomind, and Clearview outside the submitted work; being a coinventor, through Duke, on patent applications on metabolomics for Alzheimer disease, novel treatments of Alzheimer’s pending and computational models of dementia that are unlicensed. Dr Saykin reported receiving grants from the NIH during the conduct of the study; receiving grants from the NIH; receiving nonfinancial support from Avid Radiopharmaceuticals; receiving investigator-initiated research support from Eli Lilly unrelated to the work reported here; receiving consulting fees and travel expenses from Eli Lilly and Siemens Healthcare; serving as a consultant to Arkley BioTek; and receiving support from Springer-Nature publishing as Editor-In-Chief of Brain Imaging and Behavior. Dr Kaddurah-Daouk reported being an inventor on key patents (7947453, 7910301, 7682783, 7682784, 7635556, 7553616, 7550258, 7550260, 7329489, 7005255, and 6706764) in the field of metabolomics including applications for Alzheimer disease. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Results of Association of Liver Function Biomarkers With Amyloid, Tau, and Neurodegeneration (A/T/N) Biomarkers for Alzheimer Disease
Heat map of q-values of the association between liver function markers and the A/T/N biomarkers for Alzheimer disease. P values estimated from linear regression analyses were corrected for multiple testing using false discovery rate (q value). White indicates q > 0.05, red indicates significant positive association, and green indicates significant negative association. Aβ indicates amyloid-β; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; FDG, fludeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; and p-tau, phosphorylated tau.
Figure 2.
Figure 2.. Detailed Whole-Brain Voxel-Based Imaging Analysis for Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to ALT Ratio Levels Using Positron Emission Tomography (PET) Scans
Whole-brain multivariable analysis was performed to visualize the topography of the association of ALT levels and AST to ALT ratio values with amyloid-β load and glucose metabolism on a voxelwise level (false discovery rate–corrected P < .05). A, Higher ALT levels were significantly associated with reduced amyloid-β deposition in the bilateral parietal lobes. B, Increased ALT levels were significantly associated with increased glucose metabolism in a widespread manner, especially in the bilateral frontal, parietal, and temporal lobes. C, Increased AST to ALT ratio values were significantly associated with increased amyloid-β deposition in the bilateral parietal lobes and the right temporal lobe. D, Increased AST to ALT ratio values were significantly associated with reduced brain glucose metabolism in the bilateral frontal, parietal, and temporal lobes.
Figure 3.
Figure 3.. Detailed Whole-Brain Surface-Based Imaging Analysis for Alanine Aminotransferase (ALT) Levels Using Magnetic Resonance Imaging (MRI) Scans
A whole-brain multivariable analysis of cortical thickness across the brain surface was performed to visualize the topography of the association of ALT levels with brain structure. Statistical maps were thresholded using a random field theory for a multiple testing adjustment to a corrected significance level of P < .05. The P value for clusters indicates significant corrected P values with the lightest blue color. Higher ALT levels were significantly associated with greater cortical thickness, especially in bilateral temporal lobes.
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