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

INTRODUCTION

Dementia affects 5.8 million Americans aged 65 and older and 50 million people worldwide [1]. The global prevalence of dementia is projected to triple by 2050 due to population aging [2]. The lack of effective treatment for dementia highlights the critical importance of identifying markers that may have predictive value years before dementia onset, can track disease progression, and unveil underlying pathophysiological processes involved in the development of dementia. Emerging clinical and preclinical evidence suggests that early metabolic signaling alterations may contribute to risk of dementia, yet these associations are not well characterized in populations of generally healthy individuals [3, 4]. Thus, investigation into liver functions that regulate systemic metabolism may offer insights to address this gap in knowledge.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are widely used in clinical practice to detect or monitor liver damage [5]. Depending on reference populations and laboratories, ALT values below 19–33 U/L and AST values below 20–40 U/L are usually defined as a normal physiologic range [5], without specific signs or symptoms, characteristic liver pathology or laboratory findings indicative of ‘low-normal’ levels of ALT and AST [6, 7]. Nevertheless, ‘low-normal’ levels of ALT or AST among older adults are reported to be associated with frailty, sarcopenia, and the risk of mortality [8–14]. Moreover, a recent report documented lower levels of ALT and AST in patients with a dementia diagnosis compared to the levels in cognitively intact individuals, as well as reduced brain glucose metabolism and increased amyloid-β deposition among the former [15]. The authors proposed that liver hypometabolism, indexed by low levels of ALT and AST, plays a role in the pathogenesis of dementia [15]. Because the analyses were cross-sectional, reverse causation cannot be ruled out, however. In this context, the aim of our study was to evaluate whether low levels of ALT and AST, even those considered to be in the physiologic range are associated with higher risk of dementia over the course of 20 years of follow-up in the population-based Atherosclerosis Risk in Communities (ARIC) Study.

METHODS

RESULTS

Of 10,100 cohort participants free of dementia at baseline, 55.0% were women, 21.5% were black, and the mean age was 63.2 (SD 5.7) years. The median value of ALT was 16.7 U/L with an interquartile interval of 13.4–22.1 U/L. The corresponding estimates for AST were 21.9, 18.7–25.1 U/L. As shown in Table 1, mean age, BMI, blood pressure levels, lipid profiles, and proportion of never smoked cigarettes were comparable by categorized levels of ALT. Participants at lower levels of ALT were more likely to be female, black, less educated, and carriers of the APOE ɛ4 allele; in addition, they were less likely to be current alcohol consumers. A J-shaped association was observed for prevalent diabetes. A largely consistent pattern was seen across categorized levels of AST, with a few exceptions (Supplementary Table 1). A lower prevalence of APOE ɛ4 genotype but much higher prevalence of diabetes were observed in the group below the 10^th percentile of AST.

During a median follow up of 18.3 years (maximum of 21.9 years), 1,857 incident cases of dementia were ascertained and documented. The unadjusted incidence was 11.6 per 1,000 person-years in the entire study population, ranging from 10.6 per 1,000 person-years in the top quintile level of ALT to 12.6 per 1,000 person-years in the bottom < 10^th percentile of ALT (Table 1). A modestly higher unadjusted incidence than the population average was observed for <10^th percentile level of AST as well (11.9 per 1,000 person-years). Likewise, after adjusting for age, sex, and race-center, a higher incidence of dementia was observed at levels of ALT <12 U/L (Fig. 1A). A similar pattern was seen for AST (Fig. 1B).

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Fig. 1

Age, sex, race-center adjusted incidence rates of dementia over full spectrum levels of alanine aminotransferase (A) and aspartate aminotransferase (B) measured at Atherosclerosis Risk in Communities (ARIC) Study Visit 4 (N = 10,100). Alanine aminotransferase and aspartate aminotransferase were modelled continuously using linear splines, with knots at 10^th, 20^th, 40th, 60th percentiles. Dementia was ascertained by an expert adjudication panel at scheduled visits, telephone or informant interviews, or ICD-9 codes. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval.

Using multivariable Cox regression to quantify the association of plasma aminotransferases with time to incident dementia, ALT levels below the 10^th percentile were associated with a 34% higher risk of dementia compared to the second quintile adjusting for age, sex, race-center, education, and APOE ɛ4 genotype (Model 1 in Table 2, hazard ratio [HR] 1.34, 95% CI 1.08–1.65). Additional adjustment for alcohol use and diabetes (Model 2, HR 1.28, 95% CI 1.04–1.59) and other vascular and metabolic risk factors (Model 3, HR 1.27, 95% CI 1.03–1.58) did not materially change the results. The top quintile level of ALT was associated with elevated dementia risk in model 1 (HR 1.19, 95% CI 1.02–1.39), but this was no longer statistically significant after accounting for vascular risk factors. A similar pattern was observed for the association of AST with incident dementia, but of smaller magnitude (Table 2).

In general, the associations of ALT and AST with incident dementia were consistent across all subgroups explored, although differences in the magnitude of the associations were observed in some instances (Table 3, Supplementary Table 2). Specifically, we observed stronger associations of low levels of ALT and AST with dementia in white than in black cohort members. Men also showed a greater magnitude of association of low levels of AST with dementia than women. Restricting the analyses to fasting samples, additionally accounting for alcohol consumption, and for body weight did not materially alter our results, nor did the inclusion of individuals with an AST:ALT ratio ≥2 (Supplementary Tables 3–5). Finally, we confirmed an elevated risk of level 1 dementia in <10^th percentile level of ALT after accounting for attrition and selection bias (Supplementary Table 6). However, the opposite risk pattern was observed for AST.

DISCUSSION

We evaluated the prospective association between plasma aminotransferase levels and the long-term risk of dementia among 10,100 middle-aged adults who were cognitively intact, free of chronic liver disease, and had an AST:ALT ratio ≤2 (to exclude alcoholic fatty liver disease and undiagnosed advanced liver disease) at baseline. Over the course of ∼20 years, 1,857 cases of dementia accrued. Compared to the second quintile of ALT, a lower level of ALT (<10^th percentile) was robustly associated with elevated risk of dementia, even in the fully adjusted analytic model accounting for demographic, lifestyle, vascular, and metabolic risk factors. A similar pattern was seen for low levels of AST, although of smaller magnitude. The aforementioned associations were largely consistent in the subgroups explored. Our analyses considered exposure to hepatotoxic agents (e.g., habitual alcohol use and pharmacologic agents), as well as hospitalizations for non-alcoholic fatty liver disease in order to avoid potential confounding by those factors.

While a previous study identified lower levels of liver enzymes in individuals with dementia [15], our study appears to be the first to report this association in a prospective manner, years before dementia is clinically manifest. Given that hepatic metabolite profiles are altered in the presence of dementia [25, 26], identifying the temporality of this association is key to understanding the role of hepatic metabolic dysfunction in influencing the risk of dementia. Although dementias are considered metabolic disorders, most attention has been focused on brain metabolism as opposed to metabolomics in peripheral samples. Work on amyloid precursor protein/presenilin 1 (APP/PS1) mouse models described metabolic impairments in the liver, kidney and heart that affect energy metabolism, metabolism of amino acids, lipid homeostasis, oxidative stress, and hyperammonemia [27]. PS1 also interacts with glutamate transporter 1, interfering with glutamate homeostasis at the synapse. ALT and AST levels positively correlate with plasma glutamate levels, and glutamate dysregulation has been shown to precede cognitive deficits [28]. Other animal work suggests that hepatic metabolic dysregulation is associated with amyloid pathology progression. For example, metabolic dysregulation in the liver was the initial organ-specific impairment observed during amyloid pathology progression in APP/PS1 mice [29].

It has further been shown that the levels of amyloid-β in the brain reflect a balance between amyloid-β production and its clearance [30] and that amyloid-β homeostasis intersects multiple systems, including the liver [31]. Bassendine et al. assembled several lines of evidence suggesting that amyloid-β produced peripherally contributes to brain amyloid-β, that the liver is the source of brain deposits of amyloid-β, that efflux of amyloid-β to peripheral blood accounts for ∼50% of total brain amyloid-β clearance in humans, and that the liver contributes to clearance of circulating amyloid-β in the peripheral circulation [31]. Reports based on murine models document uptake, metabolization and excretion of large doses of amyloid-β by the liver [32] and in vitro work suggests that reduced hepatic degradation of amyloid-β could influence deposition of amyloid-β in the brain [33].

Other potential mechanisms speak to the plausibility of our results. Reduced liver synthesis and metabolic function, indexed by low levels of plasma aminotransferases, may contribute to or correlate with cerebral hypometabolism, which is reported to occur preceding the onset of dementia [3, 15]. As the key enzyme catalyzing the reactions from alanine and α-ketoglutarate to form pyruvate, ALT is placed at the initial step in gluconeogenesis [34]. Consequently, a reduction in ALT levels is associated with lower availability of pyruvate and may be associated with reduced gluconeogenesis in the liver and thus lower levels of glucose available as energy source to various tissues [35]. Further, we observed a higher prevalence of diabetes in the bottom decile of liver enzymes. Diabetes has been well-established as a risk factor for dementia and is associated with brain insulin resistance and impaired glucose uptake [3, 36], further linking liver hypometabolism and energy metabolism disorder in the brain.

Both ALT and AST facilitate the production of glutamate, an excitatory neurotransmitter required for the maintenance of synapses [37]. Reduced levels of ALT or AST could lead to lower levels of glutamate, a metabolite related to memory performance [15]. Moreover, low plasma aminotransferase levels are reported to be associated with poor nutritional intake and pyridoxine (vitamin B6) deficiency [12]. The active form of pyridoxine, Pyridoxal 5^′-phosphate, is a coenzyme in neurotransmitter synthesis and catalyzes transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis [12, 38]. Although requiring further elucidation, reduced levels of ALT are reportedly associated with greater structural cerebral atrophy, amyloid-β deposition, and altered neurodegenerative biomarkers in cerebrospinal fluid associated with dementia [15].

Although plasma aminotransferase levels decrease with age and dementia is strongly associated with age [8, 39], our results are unlikely to be confounded by age since the plasma aminotransferases were measured years before the onset of dementia, and analytic results stratified by age were consistent with those of the primary analysis. Moreover, the inverse association of plasma aminotransferase levels with age may be an indicator of age-associated frailty [8, 11–14] and manifestations of frailty were observed to be more prevalent at low levels of plasma aminotransferases among the members of this cohort (data not shown). Frailty has been reported to interact with cognitive impairment in accelerating the development of dementia [40]. Future studies clarifying the role of liver function in the bi-directional relationship between frailty and dementia are needed.

The association of AST with dementia was weaker than that of ALT, which merits comments. ALT is predominantly generated in the liver whereas AST can be synthesized in the liver, skeletal muscle, heart, brain, and other tissues. The greater specificity to hepatic origin of ALT adds support to the hypothesized role of liver function in the development of dementia. The greater proportion of women and of black members of the cohort in the lower range of plasma aminotransferase levels is consistent with previously observed lower ALT levels among women and black study participants compared to their counterparts [11]. It is possible that the use of uniform thresholds for plasma aminotransferase categories may blur variation by population groups in reduced and low-normal plasma aminotransferases in what is considered the physiologic range.

Our study has implications for research and public health. Whereas clinical interest in ALT and AST is mostly focused on their elevation as markers of hepatocyte damage, we examined low levels of ALT as an aminotransferase surrogate marker for loss of liver metabolic function, brain amyloid-β clearance capacity, vitamin deficiency, or lower glutamine levels among middle aged individuals free of manifest liver disease. Aminotransferase activity is a highly regulated trait, as indicted by genome-wide association studies coupled with metabolomics on the role of aminotransferase genes (e.g., GOT, GPT) in the regulation of amino acid and lipid metabolism [41]. If our results are replicated, low levels of ALT in what is deemed normal physiologic range may index reduced liver metabolism and associated health effects. Our results support the arguments that hepatic functionality should be considered for further insights into brain health and amyloid-β balance [31, 42].

Our results should be interpreted with consideration of several limitations. First, we lack biomarkers to discern the character of impairment in hepatic metabolic function. It is thus unclear what forms of liver dysfunction are indexed by the low levels of ALT and AST in free-living adults. Second, the natural history of dementia is protracted and the time of diagnosis of dementia may not accurately reflect disease inception. As a result, estimated associations with time to dementia may be underestimated. Third, dementia subsumes heterogeneous etiologic processes, whereas an etiologic classification of dementia was not available in this study. Fourth, although this study included samples of the residents of four geographic areas in the US, aged 54–73 years, generalization of our results to other populations should be done with caution. Indeed, in contrast to studies conducted among older adults, a null association of low liver enzymes with mortality was reported among younger adults [11, 43]. Lastly, some key variables such as sarcopenia were not measured and could potentially introduce residual confounding.

CONCLUSIONS

Low levels of plasma aminotransferases <10^th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia. These results advocate for attention to the putative role of hepatic function in the pathogenesis of dementia.