Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers
Authors: Kwangsik Nho, Alexandra Kueider-Paisley, Shahzad Ahmad, Siamak MahmoudianDehkordi, Matthias Arnold, Shannon L. Risacher, Gregory Louie, Colette Blach, Rebecca Baillie, Xianlin Han, Gabi Kastenmüller, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, P. Murali Doraiswamy, Cornelia van Duijn, Andrew J. Saykin, Rima Kaddurah-Daouk
Journal: JAMA Network Open (2019)

<h3>Importance</h3> 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. <h3>Objective</h3> To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD. <h3>Design, Setting, and Participants</h3> 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. <h3>Exposures</h3> 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. <h3>Main Outcomes and Measures</h3> 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 (<sup>18</sup>F) positron emission tomography, and amyloid-β accumulation measured by [<sup>18</sup>F]florbetapir positron emission tomography. <h3>Results</h3> 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];<i>P</i> = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422];<i>P</i> = .004) and poor cognitive performance (AST to ALT ratio: β [SE], −0.465 [0.180];<i>P</i> = .02 for memory composite score; β [SE], −0.679 [0.215];<i>P</i> = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128];<i>P</i> = .006 for memory composite score; β [SE], 0.637 [0.152];<i>P</i> &lt; .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];<i>P</i> = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau<sub>181</sub>(β [SE], 0.175 [0.055];<i>P</i> = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049];<i>P</i> = .02) and reduced brain glucose metabolism (β [SE], −0.123 [0.042];<i>P</i> = .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];<i>P</i> = .02) and greater atrophy (neurodegeneration biomarkers). <h3>Conclusions and Relevance</h3> 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.