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Review

Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain

by
Matina Kouvari
1,2,3,*,
Domenico Sergi
4,
Nathan M. D’Cunha
1,3,
Amanda Bulman
1,3,
Demosthenes B. Panagiotakos
1,2,3 and
Nenad Naumovski
1,2,3,*
1
Functional Foods and Nutrition Research (FFNR) Laboratory, University of Canberra, Ngunnawal Country, ACT 2617, Australia
2
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 10431 Athens, Greece
3
Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, ACT 2601, Australia
4
Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
*
Authors to whom correspondence should be addressed.
Diabetology 2022, 3(2), 355-363; https://doi.org/10.3390/diabetology3020026
Submission received: 18 April 2022 / Revised: 7 June 2022 / Accepted: 11 June 2022 / Published: 14 June 2022
(This article belongs to the Special Issue Brain and Diabetes)
Review Reports Versions Notes

Abstract

:
The prevalence of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), is increasing in parallel with the rising rates of obesity and type 2 diabetes. Approximately one in four adults are diagnosed with liver steatosis globally. NAFLD is associated with insulin resistance, hypertension, obesity, visceral adiposity, and dyslipidaemia. These risk factors are often accompanied by inflammation and oxidative stress, which also play a role in extrahepatic diseases, including conditions related to the central nervous system, such as mild cognitive impairment and Alzheimer’s disease. The number of people living with dementia is approximately 55 million and is estimated to increase to approximately 2 billion people by 2050. Recent studies have found that NAFLD is associated with poorer cognition. The aim of this review was to summarise the findings of hitherto studies that have linked NAFLD with cognition and dementia, as well as to discuss the potential liver–brain pathways.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, affecting approximately 25% of the general population [1]. NAFLD rates are rising in parallel with the pandemics of obesity and type 2 diabetes mellitus (T2DM) [2]. NAFLD occurs in the absence of excessive alcohol consumption and is closely associated with metabolic syndrome (MetS) and its components [3]. Indeed, it represents the hepatic manifestation of the MetS. Additionally, NAFLD has metabolic and cardiovascular consequences that have been linked with metabolic complications, chronic kidney disease, cardiovascular disease (CVD), and malignancies, contributing to higher mortality. The latter is common in people with non-alcoholic steatohepatitis (NASH), which is characterised by both hepatic steatosis and inflammation [4]. All of these conditions related to NAFLD share low-grade inflammation and oxidative stress as common features, which, in turn, also play a role in extrahepatic diseases. In this context, the literature suggests an interaction between the liver and brain, adding one more indication regarding the intercorrelation between neurological and metabolic systems [5].
Worldwide, approximately 55 million people are living with dementia, and over 60% are living in low and middle-income countries. As the proportion of older people is increasing globally, this number is expected to rise to 78 million by 2030 and 139 million by 2050 [6]. Various pathophysiological conditions have been linked with cognitive dysfunction, such as obesity, systemic inflammation, T2DM, and vascular dysfunction, all frequently co-existing with NAFLD [7]. Changes in cognition related to NAFLD have only recently become a topic of clinical and scientific interest, and the implications of metabolic encephalopathy on the cognitive decline are not well-defined in human studies [7]. Several observational studies have investigated the association between NAFLD and various features of cognitive performance with mixed outcomes. The aim of the present work was to summarise the findings of studies investigating the association of NAFLD with cognition and cognitive impairment (any kind) and to discuss potential underlying mechanisms.

2. Search Strategy

The literature searches were performed on electronic databases Medline (PubMed), Embase, Scopus, Cochrane Central Register of Controlled Trials databases, and ISI Web of Knowledge for manuscripts that examined the association between NAFLD and cognition and/or cognitive impairment (any kind). The search strategy was as follows: (“Cognit*” OR “dementia” OR “Alzheimer’s disease”) AND (“NAFLD” OR “NASH” OR “liver steatosis” OR “liver fibrosis” OR “liver” OR “Nonalcoholic fatty liver” OR “non-alcoholic fatty liver”). The search was limited to publications in English until March 2022. The reference lists of retrieved articles were also considered when these were relevant to the issue examined yet not allocated in the basic search.

3. Observational Studies on the Association between NAFLD and Cognition

Within the last decade, only 11 observational studies have evaluated the association between NAFLD and cognition, with the vast majority published in the last 4 years [8,9,10,11,12,13,14,15,16,17,18,19,20,21]. The findings of these studies are summarised in Table 1. Five studies prospectively examined this association, presenting contradicting outcomes. The CARDIA study included middle-aged participants from the USA and revealed that the presence of NAFLD did not significantly affect the cognitive decline in a 5-year follow-up [9]. On the other side, a prospective study from a Chinese cohort revealed that NAFLD participants had greater cognitive decline compared with their free-of-NAFLD counterparts during a 4-year follow-up, especially within the subgroup of middle-aged individuals. Three studies in Europe—one in Italy, one in Germany, and one in Sweden—investigated the effect of NAFLD on long-term dementia risk, revealing either positive [19] or neutral [18,21] associations. However, in the case of the study from Sweden, once the histological features of liver steatosis were included in the model that predicted dementia risk, this significantly increased its predictive ability [21]. The remaining nine studies had a cross-sectional [10,11,12,13,15,17] or case-control [14,16,20] design. Only one of them, a sub-analysis in the Framingham study, revealed non-significant associations between NAFLD and cognition assessed via neuropsychological tests [11]. Four studies [8,13,14,16] evaluated the association between NAFLD and general cognitive performance using multiple neuropsychological tests. All of these studies reported that individuals with NAFLD had significantly lower cognitive performance overall, measured via different validated questionnaires. Three studies revealed significantly lower processing speed and attention in people with NAFLD compared with non-NAFLD controls [10,16,17]. Memory and learning domains were examined in three studies revealing mixed outcomes [11,16,17]. In particular, one study reported lower performance in memory and learning test scores within the NAFLD group [17], while no significant associations were identified in the other two studies. In one study [15], the association between NAFLD and the language domain of cognitive performance was evaluated, revealing lower scores in the presence of this pathophysiological condition. Three studies investigated the role of NAFLD on visuospatial perception [11,13,16]. Two out of the three studies found poorer visuospatial perception in people with NAFLD [13,16]. In addition to this, NAFLD was associated with lower scores in abstraction, figural creation, and mental flexibility, as revealed by three studies [10,11,16]. Brain aging was assessed in one study with individuals that were free of NAFLD having lower aging of the brain compared with their NAFLD counterparts [12].

4. Pathogenetic Mechanisms Underpinning the Development of NAFLD

NAFLD represents the hepatic manifestation of the MetS. From a pathogenetic perspective, it arises as a consequence of an imbalance between triglyceride synthesis, fatty acid supply to the liver, triglyceride export via very-low-density lipoprotein (VLDL), and fatty acid oxidative capacity by the liver. This imbalance ultimately leads to the intrahepatic accumulation of triglycerides. Remarkably, all of these processes occur in a state of systemic insulin resistance and compensatory hyperinsulinemia [22]. Indeed, in the context of obesity and MetS, the underlying state of low-grade chronic inflammation promotes insulin resistance in metabolically active tissues, including adipose tissue [23]. Adipose tissue insulin resistance leads to an increase in fatty acid spill over from adipocytes due to the disinhibition of lipolysis [24]. This contributes to fatty acid oversupply in the liver, thereby fuelling the accumulation of triglycerides as lipid droplets within the hepatocytes. In support of the importance of this process in promoting NAFLD, the knockdown of fatty acid transport protein (FATP) 5, a fatty acid transporter expressed by hepatocytes, reversed steatosis in mice [25]. Another key pathogenetic process underpinning the accumulation of intrahepatic triglycerides is enhanced de novo lipogenesis, which is also a direct consequence of insulin resistance and, particularly, the compensatory hyperinsulinemia. De novo lipogenesis is under the transcriptional control of sterol regulatory element-binding protein 1c (SREBP1c), which, in turn, is regulated by insulin. However, de novo lipogenesis is not inhibited by insulin resistance. Instead, it is enhanced by hyperinsulinemia, which explains the increased hepatic de novo lipogenesis under insulin-resistant conditions [26]. A further pathogenetic mechanism underpinning the onset and progression of NAFLD is represented by impaired fatty acid oxidation, a metabolic pathway under the control of PPARα. In support of the role of this nuclear receptor and impaired fatty acid catabolism in the pathogenesis of NAFLD, PPARα-deficient ob/ob mice manifest more severe hepatic steatosis compared to their littermates due to decreased fatty acid oxidation [27].
However, data in humans relative to the relationship between fatty acid oxidation and NAFLD is controversial, with studies reporting either an increase, a decrease, or no changes in lipid catabolism in individuals with NAFLD [28]. Nevertheless, it must not be overlooked that even when there is an increase in fatty acid oxidation, the magnitude of such an increase may not be sufficient to cope with enhanced fatty acid supply. This compensatory response marked by an increase in fatty acid oxidation promotes an increase in reactive oxygen species (ROS), which further contributes to the mitochondrial dysfunction that characterises NAFLD [29]. In turn, mitochondrial dysfunction, due to the role of these organelles in fatty acid β-oxidation, contributes to both the inability of hepatocytes to cope with increased fatty acid supply as well as ROS production [30]. Finally, defects in triglycerides exported from the liver also contribute to NAFLD. In parallel with increased fatty acid oxidation, enhanced triglyceride export as part of VLDL also represents a mechanism to decrease hepatic lipid accumulation [31]. Once produced in the endoplasmic reticulum of hepatocytes, VLDL is channelled towards the Golgi apparatus, where mature VLDL are formed. In the context of NAFLD, there is an increase in VLDL secretion, which plateaus once hepatic lipid content exceeds 10%, thereby promoting hepatic triglyceride accumulation [32]. Additionally, in people with hepatic steatosis, rather than the number of VLDL particles, there is an increase in the size of secreted VLDL, which, due to their size, are secreted less effectively, leading to lipid retention in the liver [33].

5. Interpretation of the Liver-Brain Axis: Suggested Mechanisms

Several mechanisms may explain the putative connection between NAFLD and cognition. Insulin resistance and progressive lipid deposition in the liver, the hallmark of NAFLD, lead to an increase in peripheral hyperinsulinemia, lipid peroxidation, and systemic inflammatory damage in brain cells [34]. NAFLD, NASH, and other liver diseases may also lead to hyperammonemia, principally when they are progressing to cirrhosis [35]. Increased levels of ammonia combined with the aforementioned inflammation as well as insulin resistance have been associated with cognitive impairment [36]. Conditions such as obesity, diabetes, and MetS commonly co-exist with NAFLD and contribute to impaired vascular function, which, in turn, impact the central nervous system exacerbating poorer cognitive health [37,38]. This is in line with evidence that the observed cognitive decline in middle-aged individuals is associated with conditions such as adiposity [39]. The evidence presented in this review implies a similar association in the case of NAFLD.
Furthermore, we will discuss the physiological and mechanistic aspects, potentially underpinning the suggested link between NAFLD and cognition impairment. In particular, a. systemic inflammation and neuroinflammation, b. liver–gut axis and disturbed gut microbiota c. vascular dysfunction, and d. neurodegeneration.

6. Systemic Inflammation and Neuroinflammation

Neuroinflammation is considered a principle underlying mechanism in cognitive dysfunction and neurodegenerative disorders [38,40]. NAFLD is characterised by low-grade inflammation starting from tissues such as the liver and gut and steadily affecting other organs, including the brain [3,41]. In the liver, this pathophysiological condition results in chemokines being released from hepatocytes and non-parenchymal cells. Chemokines further promote the activation of liver-resident macrophages, which then lead to the release of proinflammatory cytokines. Once the systemic inflammation reaches the brain, neuroinflammation may occur. Cytokines can cross the blood–brain barrier (BBB) through active transport or direct entry in circumventricular regions where the BBB is absent, affecting the central nervous system [42]. In particular, BBB integrity results from the integration of signals within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells. Early BBB breakdown in cases of metabolic conditions is mainly due to increased oxidative stress, including ROS [43]. Additionally, circulating cytokines have the potential to activate their receptors on endothelial cells in the hypothalamus, enhancing the release of inflammatory factors inside the central nervous system [44]. Another hypothesis is that the locally produced cytokines may activate afferent nerves that project to several regions in the central nervous system [40]. Neuroinflammation is also a local process characterised by the activation of resident immune cells, the microglia. All these paths lead to a complex immune response characterised by the release of proinflammatory cytokines [45].

7. Liver–Gut Axis and Disturbed Gut Microbiota

NAFLD and other liver diseases present with compositional and functional alterations of gut microbiota, known as gut dysbiosis, characterised by reduced gut microbiota diversity and potential overgrowth of pathogenic taxa (pathobionts). Reduced microbiota diversity and imbalance in healthy vs. pathogenic microbes are associated with many metabolic or immune-mediated disorders [46,47]. Additionally, in many people with NAFLD or NASH, there is an increased ratio between the two phyla, Firmicutes and Bacteroides [48]. These microbial abnormalities are drivers of leaky gut, a common feature in NAFLD where tight junction proteins anchoring to intestinal endothelial cells lose their sealing effect, subsequently increasing mucosal permeability and endotoxin transport [49]. Metabolites and bacterial fragments reach the liver through the portal vein resulting in hepatic inflammation, lipogenesis, oxidative stress, and fibrogenesis [22]. In addition to this, bacterial by-products such as endotoxins, ammonia, and bacterial DNA propagate systemic inflammation and neuroinflammation [50]. Considering that people with NAFLD or NASH present with altered gut microbiota and impaired gut health has been widely associated with cognitive dysfunction, it may suggest another underlying path through which cognitive dysfunction is exhibited in liver steatosis. Nevertheless, the evidence that connects these two conditions is scarce and only in animal-based models. In particular, a rat NASH model with gut dysbiosis and reduced production of gut microbial short-chain fatty acids was associated with neurobehavioral dysfunction [51]. Another interesting finding comes from a rat NASH model treated with probiotics for 2 weeks, revealing ameliorations in spatial learning and memory in the post-intervention phase with a simultaneous increase in viable cells of the hippocampal region [52]. These preliminary findings imply an important association between gut microbiota and cognitive dysfunction in NAFLD either through the gut–liver axis or through their interaction with the brain. In addition, due to the intricate and yet-to-be fully elucidated relationship between cognition and the gut microbiota, the effects of probiotic interventions in NAFLD deserve further investigation [53].

8. Vascular Dysfunction

NAFLD—due to systemic proinflammatory and procoagulant factors—is independently linked with carotid intima-media thickness, coronary calcification, endothelial dysfunction, arterial stiffness, and other subclinical atherosclerosis markers [54]. This vascular dysfunction in NAFLD has been previously associated with cognitive dysfunction as well [14]. In a study of 80 people with NAFLD and 83 controls, endothelial dysfunction was significantly associated with lower cognitive scores compared with controls [14]. In addition, NAFLD is associated with increased risk and severity of a stroke, and there is preliminary evidence suggesting a link between NAFLD and subclinical cognitive impairment [55]. NAFLD is associated with asymptomatic brain lesions and changes in cerebral perfusion, which contribute to the risk of vascular dementia, which is the second most common type of dementia [55].

9. Neurodegeneration

Two cohort studies investigated the association between NAFLD and long-term dementia risk with contradicting outcomes [18,19]. Towards the hypothesis that NAFLD results in neurodegeneration, which, in turn, contributes to various features of cognitive impairment, a recent network clustering analysis showed a gene-based correlation between NAFLD and Alzheimer’s disease. Specifically, it has been suggested that these two pathophysiological conditions share 189 genes [56] involved in carbohydrate metabolism, long fatty acid metabolism, and interleukin 17 (IL-17) signalling pathways [56]. Considering the major role of the insulin/insulin growth factor I (IGF-I) pathway in Alzheimer’s disease, peripheral insulin resistance in NAFLD may mediate this association [57]. Indeed, prediabetes and T2DM increase the risk of dementia, and incidence can be predicted by several biomarkers used in the management of diabetes, including HbA1c and fasting plasma insulin [58]. Brain insulin resistance is sometimes referred to as “Type 3 Diabetes” because of common molecular and cellular characteristics between T2DM and Alzheimer’s disease, particularly insulin dysregulation [59]. A study in rats showed that induced NAFLD and insulin resistance were associated with hyperglycaemia, hyperlipidaemia, and lower brain glucose levels, demonstrating an association with the impaired brain energy metabolism that is observed in Alzheimer’s disease [60]. Therefore, further research is needed to examine the associations between NAFLD and its pathological characteristics common to common types of dementia in order to design targeted interventions that can potentially prevent cognitive decline before symptoms appear.

10. Conclusions

People with impaired liver health due to NAFLD seem to constitute a heterogeneous group from the standpoint of cognition. This is currently explained by several mechanistic hypotheses based on increased systemic inflammation and neuroinflammation, mediated via the gut–liver–brain axis, then endothelial and vascular dysfunction, and eventually underpinning neurodegeneration. Future research should invest in characterising the cognitive profile of people with NAFLD in well-defined subgroups to attain a better interpretation of this complexity as well as to allow for more efficient therapies.

Author Contributions

Conceptualisation, M.K. and N.N.; methodology, M.K.; formal analysis, M.K., D.S., N.M.D., A.B., D.B.P. and N.N.; resources, M.K. and N.N.; writing—original draft preparation, M.K.; writing—review and editing, M.K., D.S., N.M.D., A.B., D.B.P. and N.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funcing.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Table
Table 1. Characteristics of selected observational studies on the association between non-alcoholic fatty liver disease and cognitive function (n = 11).
Table 1. Characteristics of selected observational studies on the association between non-alcoholic fatty liver disease and cognitive function (n = 11).
Author, YearStudy Name (If Any)Study DesignCountryAge—CategoryStudy SampleNAFLD DiagnosisCognitive Function AssessmentMain ExposureMain OutcomeLevel of AssociationConclusion
Liu, Q., 2022-prospectiveChinamiddle-aged and older people1651Abdominal ultrasonographyMini-Mental State Examination (MMSE)NAFLD presenceGlobal cognitive function4-year prospective associationNAFLD associated with cognitive decline, especially in middle-aged and with carotid stenosis population.
Gerber, Y., 2021CARDIA studyprospectiveUSAmiddle-aged2809Computed tomography (CT) examinationBattery of 3 cognitive tests: Digit Symbol Substitution Test (DSST), the Rey Auditory Verbal Learning Test (RAVLT), and the Stroop TestNAFLD presenceScores in cognitive testsCross-sectional/5-year prospective associationNAFLD presence associated with lower cognitive performance/NAFLD presence not significantly associated with cognitive decline in 5-year follow-up.
Labenz, C., 2021-prospectiveGermanyolder people22,317 patients/22,317 controlsICD-10 codingDementiaNAFLD presenceDementia risk10-year prospective associationNo independent association with dementia incidence was detected.
Shang, Y.,
2021		-nested case-cohortSwedenmiddle aged and older people656Liver BiopsyDementiaNAFLD presenceDementia risk20-year prospective associationNo association between NAFLD and dementia risk in an almost 20-year follow-up. Histological markers to a conventional risk model for dementia enhanced its predictive ability.
Solfrizzi, V., 2020Italian Longitudinal Study on AgingprospectiveItalyolder people1061NAFLD fibrosis score (NFS)DementiaNFS categorizationDementia risk8-year prospective associationAdvanced liver fibrosis (F3-F4 NFS) could be a long-term predictor for overall dementia risk.
Weinstein, G., 2019FraminghamprospectiveUSAmiddle-aged and older people1287Multi-detector computed tomography scansNeuropsychological test (Wechsler Memory Scale)NAFLD presenceLogical Memory Delayed Recall (LMd); Visual Reproduction Delayed Recall (VRd); Trail making B minus Trail making A (TrB-TrA); Similarities test (SIM); Hooper Visual Organization test (HVOT)Cross-sectionalNAFLD per se not associated with cognitive performance. Advanced fibrosis associated with poorer performance on tests assessing executive function and abstract reasoning.
Weinstein, A. A., 2018NHANEScross-sectionalUSA>65 years old1102Fatty liver index score ≥ 60Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-WL); Animal Fluency Test; digit symbol substitution testNAFLD presenceScores in cognitive testsCross-sectionalNAFLD with or without type 2 diabetes performed significantly worse on a task that requires a combination of processing speed, sustained attention, and working memory.
Filipović, B., 2018-cross-sectionalSerbiamiddle-aged76Ultrasonography (US)MRI brain scanning combined with Montreal Cognitive Assessment (MoCA) testNAFLD presenceMoCA scoreCross-sectionalNAFLD significantly influenced cognitive deficit and tissue volume reduction and people suffering from NAFLD had about four times higher risk of having a cognitive impairment.
Tuttolomondo, A., 2018-case-controlItalymiddle-agedControl: 83/Cases: 80Liver biopsy; ultrasonography (US); liver stiffnessMini-Mental State Examination (MMSE)NAFLD presenceGlobal cognitive functionCross-sectionalNAFLD subjects lower mean MMSE scores in comparison with control subjects without NAFLD.
Weinstein, G., 2018FraminghamprospectiveUSAolder people766Multi-detector computed tomography scansBrain magnetic resonance imagingNAFLD presenceTCBV (years of brain aging)Cross-sectionalNAFLD associated with brain aging.
Elliot, C., 2013-nested case-cohortUSAmiddle aged and older people224Histological diagnosisCognitive Failures QuestionnaireNAFLD presencefrequency of cognitive slips or failures occurring in everyday
life		Cross-sectionalNAFLD patients presented worse function independently associated with
cognitive symptoms, compared with their age-matched controls.
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Kouvari, M.; Sergi, D.; D’Cunha, N.M.; Bulman, A.; Panagiotakos, D.B.; Naumovski, N. Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain. Diabetology 2022, 3, 355-363. https://doi.org/10.3390/diabetology3020026

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Kouvari M, Sergi D, D’Cunha NM, Bulman A, Panagiotakos DB, Naumovski N. Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain. Diabetology. 2022; 3(2):355-363. https://doi.org/10.3390/diabetology3020026

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Kouvari, Matina, Domenico Sergi, Nathan M. D’Cunha, Amanda Bulman, Demosthenes B. Panagiotakos, and Nenad Naumovski. 2022. "Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain" Diabetology 3, no. 2: 355-363. https://doi.org/10.3390/diabetology3020026

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