Low Liver Enzymes and Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia.

Serum clinical laboratory tests and risk of incident dementia: a prospective cohort study of 407,190 individuals

“…2), individuals with lower liver enzyme alanine aminotransferase (ALT, HR 0.990, 95% CI: 0.986-0.995, p = 2.6E-04) have a higher dementia incidence. Similar relationships were also observed by Kwangsik [16] and Yifei [8]. The cubic spline model showed a significant nonlinear J-shaped association between ALT and risk of dementia (P for nonlinearity = 0.007; Fig.…”

“…Reduced liver synthesis and metabolic function, indexed by decreased ALT levels [16], have shown to be linked with higher dementia risks. As the key enzyme catalyzing the process of pyruvate formation from alanine and α-ketoglutarate, reduced ALT associated with lower availability of pyruvate and may be related to decreased gluconeogenesis in the liver, therefore result in lower levels of glucose available as energy source to various tissues, especially in the orbitofrontal cortex and temporal lobes, brain regions implicated in executive and memory function [8,16]. Furthermore, liver dysfunctions might lead to decreased livermediated clearance of peripheral Aβ, which may be a mechanism underlying dementia [29,30].…”

“…With the increasing prevalence of dementia and lack of effective treatments [2], current trends show that identifying novel biomarkers and searching for modifiable risk factors to counteract the dementia epidemic with non-invasive methods are in demand [3]. So far, the most frequently mentioned in published studies are inflammatory markers such as interleukin 6 (IL-6), cytokines and C-reactive protein (CRP) [4,5], neurotrophic factor, immunometabolic markers [6,7], liver enzymes [8,9], and metabolism damage markers [10], some of which may reflect comorbid diseases but are closer to the potential pathophysiology and less susceptible to diagnostic bias. Nevertheless, establishing robust and reliable indicators remains a challenge, possibly due to publication bias, confounding, small sample size, insufficient follow-up time, and neglect of possible nonlinear relationship.…”

Machine Learning Analysis Reveals Biomarkers for the Detection of Neurological Diseases

“…Regarding the multinomial model, deconstruction of the model weightings revealed directional machine-learned associations between clinical markers and diseases ( Supplementary Table 5 ). Some of these associations have already been reported in the literature: for instance, our model predicted low ALT in AD, which is consistent with the literature (Lu et al, 2021 ). Our model also correctly predicted low apolipoprotein A in AD, PD, and MND (Qiang et al, 2013 ; Mariosa et al, 2017 ; Zuin et al, 2021 ) and elevated calcium in AD and PD (Zakharov et al, 2007 ; Angelova et al, 2016 ; Ryan et al, 2020 ).…”

Machine learning analysis reveals biomarkers for the detection of neurodegenerative diseases

“…In the case of ALT, this association of low ALT with AD is consistent with the literature (Lu et al, 2021). Other brain diseases such as intracerebral haemorrhage have been linked with elevated ALT (Nho et al, 2019).…”