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].

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.