The Link between Metabolic Syndrome and the Brain

In 1988, Reaven [1] proposed for the first time a cluster of cardiovascular risk factors including hyperinsulinemia, dysglycemia, hypertriglyceridemia, abnormal high-density lipoprotein (HDL) cholesterol levels, and hypertension that he named “syndrome X” [1, 2]. Later syndrome X was renamed to metabolic syndrome (MetS), and in 1988, the World Health Organization (WHO) introduced the first definition criteria for the condition [2, 3]. Nowadays, the most common criteria used to define MetS are the 2005 revised NCEP-ATP III, which include the presence of at least 3 of the following risk factors: waist circumference over 40 inches in males or 35 inches in females, elevated blood pressure (>130/85 mm Hg), elevated fasting triglyceride level (>150 mg/dL), low fasting HDL cholesterol level (<40 mg/dL in males or <50 mg/dL in females), and fasting blood sugar over 100 mg/dL [4].

The use of MetS in clinical practice helps to identify a subgroup of patients at higher risk for cardiovascular disease and allows physicians to communicate and understand the underlying pathophysiologic process which is common in this subset of patients [4]. In addition to cardiovascular disease, MetS has been associated with cerebrovascular accidents, hepatic steatosis, and several malignancies [5‒7]. More recently, concerns have been raised that the MetS is associated with an increased risk of cognitive decline [8‒13]. The incidence of MetS is directly proportional to the incidence of diabetes mellitus (DM) type 2 and obesity [14]. However, despite the availability of accurate data to calculate the prevalence for both DM and obesity, obtaining data for MetS is substantially harder, especially considering the variety of definitions that have been proposed [14]. Currently, it is estimated that MetS prevalence is three times higher than DM and affects about one-quarter of the world population [14]. One of the largest studies in 2017, conducted by CDC, used the criteria published in joint scientific statement for MetS diagnosis and analyzed MetS trends between 1988 and 2012. The study revealed that in 2012, more than one-third of all US adults met the criteria for MetS, with the highest burden being among non-Hispanic African American population [15]. It was concluded that further increases in MetS prevalence are to be expected in the future [15].

MetS is associated with lower cognitive performance, increased risk of minimal cognitive impairment (MCI), MCI progression, and vascular dementia (VaD) [8‒13]. On the other hand, data for Alzheimer’s disease (AD) are conflicting. Some authors suggest a protective role of MetS, while others find either no association or an increased risk of AD in patients with MetS [9, 11, 13, 16]. MetS increases the risk of all-cause dementia, especially in long-term studies (10–25 years), highlighting the effects of long-term exposure to multiple metabolic risk [8, 9, 17]. Fan et al. [18] report that only patients with worsening MetS have higher dementia rates and patients with persistent MetS may be adapting to MetS effects through long-term exposure The studies that have been conducted show an association between MetS or its components and cognitive dysfunction [19, 20]. Even though most studies have revealed this link, the current body of evidence is characterized by several weaknesses, including but not limited to lack of a consistent MetS definition, lack of consistent cognitive function measurement, and survival bias. These have resulted in several contradictions. For example, in the elderly, MetS was found to be a protective factor against dementia [11, 21]. Moreover, even though there are several hypotheses, currently, there is no strong theory regarding the underlying pathophysiologic mechanism in the relationship between MetS and cognitive dysfunction. The current narrative review discusses evidence of the association between MetS and cognitive disorders and highlights putative risk factors and pathophysiology mechanisms characterizing this relationship.

When three or more metabolic risk factors are combined, the risk for dementia development increases substantially, and for each additional factor, it becomes even higher [19, 20]. High rates of dementia are associated with hypertriglyceridemia, abdominal obesity, and hypertension, even though some studies suggest that hypertension and dyslipidemia do not increase the risk of MCI progression [10, 20, 22]. However, midlife total cholesterol levels can predict dementia in general population [10]. Body mass index (BMI) is associated with cognitive decline; a higher BMI is linked to poorer cognitive function [23]. In a recent study in China that established association between MetS and cognitive dysfunction, the main driver underlying that link was found to be obesity. However, while some studies indeed have confirmed the association between midlife obesity with dementia, others in Asia have shown that high BMI is associated with better cognition [24]. Glucose metabolism dysregulation is consistently associated with cognitive dysfunction [25]. Hyperglycemia has been proposed as the main contributor in the association between cognitive decline and MetS [12]. In the setting of MCI, patients with DM exhibit higher rates of progression to dementia [20]. Patients with DM and MetS have lower performance in multiple cognitive domains. Simultaneously, in patients with MetS, lower HbA1C levels (<7%) are associated with improved cognitive performance. Longer DM duration (5 years or longer) and higher mean blood glucose levels lead in up to 40–60% higher risk for dementia [20, 23]. High blood glucose levels during midlife result in long-term brain insults and as such may lead to cognitive decline and dementia [25]. Moreover, even prediabetes has been reported to increase risk for MCI progression [10, 22]. Hyperinsulinemia, a consequence of insulin resistance states, is associated with cognitive decline, AD, and VaD [10, 22]. As such, it is evident that even though cardiometabolic risk factors have been heavily investigated in relation to cognition, only glucose intolerance has demonstrated a strong association with cognitive decline. Longer DM duration, higher HbA1C, and higher glucose levels show a statistically significant association with worse cognitive function. Given the glucose intolerance central role in MetS, this may be the underlying pathophysiologic connection between MetS and cognitive dysfunction [20, 23, 25].

MetS and cardiometabolic risk factors are linked to faster decline and worse performance in at least one of the main domains (i.e., memory, language, verbal fluency, executive function, construction, visuoconstruction, and mental function) [11, 17, 25, 26]. However, for domains such as global cognition, conflicting data exist. Some studies reveal no association between MetS and global cognition, while others suggest that the MetS is protective among the older population in this domain [8, 11, 26, 27]. The association between MetS and executive function is also unclear [11, 26, 28, 29]. Elevated blood pressure, impaired glucose metabolism, longer waist circumference, and low HDL are strongly associated with poor memory [30]. A study proposed that elevated blood glucose and abdominal obesity may be driving a lower performance not only in memory but also in attention domains, while another study associated these factors with lower performance in motor speed and psychomotor coordination [28, 30]. McEvoy et al. [29] revealed that patients with MetS and DM are at increased risk for decline in executive control. However, this did not apply in patients with MetS without DM [29]. The different criteria used by studies to diagnose MetS may introduce bias and lead to these discrepancies. Patients meeting different criteria may have different metabolic and cognitive profiles. Moreover, some studies use different cutoffs introducing misclassification bias. Another source of bias may be the availability and utilization of various cognitive tests [26]. In future studies, investigators are encouraged to use the most widely accepted definition for MetS and standardized tests to assess cognition and cognitive domains.

The Mediterranean diet, higher omega-3 fatty acids or vegetable consumption, and higher exercise levels may act as protective factors against cognitive dysfunction in patients with MetS, leading to lower risks of MCI development/progression [10, 20, 31]. In contrast, food addiction is associated with prominent cognitive decline [31]. As such, it is evident that healthy dietary habits can protect against cognitive decline in people with MetS and early dietary interventions are encouraged [32].

The role of education and socioeconomic status is also important. A modest protective impact of education and strong protective impact of occupation on the MetS-dementia relationship suggest that socioeconomic factors may be an underlying confounding factor in the MetS-cognition relationship [17]. Subjects with MetS lacking tertiary education exhibit lower speed of reaction, poor memory functions, and overall cognitive decline [30]. Higher education may be a protective factor against cognitive decline among the elderly (>70 years old) with MetS as higher education results in effective brain stimulation in young age and protects against brain pathologies that may affect cognition later in life [33].

MetS and cognitive function relationship is different in various age-groups. MetS is associated with lower cognitive function in patients younger than 70 years old but not in older patients [34]. Younger population tends to exhibit much stronger the consequences that MetS has on cognition [34].

In elderly patients (65–80 years of age and older), there is no significant association between MetS and cognitive performance. Some studies support that MetS may even have a protective role against cognitive dysfunction and dementia in that group [8, 9, 21, 22, 28, 35]. Laudisio et al. [21] suggests that abdominal obesity and low HDL may play a role against cognitive decline in older women. Crichton et al. [11] revealed that in people 85–90 years old, upon 5 years follow-up, those with MetS had a slower cognitive decline than younger patients. Assuncao et al. [25] concluded that it cannot be determined whether MetS is a risk factor for cognitive decline in elderly patients (75–80 years of age or older).

Investigators suggest that the age-related discrepancies observed may be explained by the changing role of the conditions defined as cardiometabolic risk factors with aging [25]. Moreover, the thresholds used to diagnose MetS and cardiometabolic components may differ with age, which is not accounted for in current studies [25, 35]. The adaptive changes associated with aging may result in different body composition, vascular physiology, and metabolism, which could be protective (instead of harmful). For example, hypertension and higher BMI in later life may be protective against cognitive decline and dementia by preserving adequate cerebral perfusion [22, 25]. Indeed, even though cardiometabolic risk factors have been associated with dementia in younger adults, this did not apply in older patients [19]. Despite these results, survival bias is a limitation in these studies [21, 22, 34, 35]. Further studies are needed to clarify whether cardiometabolic risk factors truly have a protective role against cognitive decline in the elderly or the current observations are results of survival, misclassification, or other bias.

Overall, the major factors contributing to cognitive decline in MetS include insulin resistance, inflammation, atherosclerosis, and ischemic brain injury [8, 20]. Insulin resistance is associated with accelerated decline in memory, global cognition, and reduced frontal cortex function [9, 34]. Compensatory hyperinsulinemia in insulin resistance states lowers the levels of insulin transported across the blood-brain barrier and results in lower insulin for use in the central nervous system [34, 36]. Insulin acts as a neuromodulator controlling amyloid concentrations. Impaired signaling may eventually contribute to the development of dementia by affecting key cognitive areas [16, 37]. The MetS is a low-grade pro-inflammatory state, and elevated inflammatory markers have been associated with an increased risk of dementia development [9]. Studies show a greater rate of cognitive decline in patients with elevated CRP and IL-6 [27, 38]. Inflammation and endothelial dysfunction in patients with MetS may lead to neurological degeneration [30]. Inflammation can contribute to accelerated atherosclerosis and in combination with diabetes lead to cognitive impairment [38]. Vascular brain pathology is important in cognitive dysfunction in MetS [33]. An active brain region has high neuronal activity and metabolic waste (carbon dioxide, lactate, heat, other metabolites). The clearance of these byproducts is necessary for the unimpeded functioning of the brain, and for this reason, topical vasodilation is observed in active brain areas. In patients with MetS due to inefficient vasoreactivity, this process may be defective and may result in a suboptimal neuronal environment [36] (Fig. 1).

MetS is associated with recurrent and silent strokes, eventually leading to high stroke volume and high risk for VaD development [9]. Frontal brain regions are vulnerable to vascular disease and cerebrovascular factors, explaining the consistently worse performance in executive function observed in patients with MetS [8].

The influence of the gut microbiome on CNS has been highlighted in multiple studies, suggesting that the gut microbiota play a role in dementia development [32]. Composition of the gut microbiome is closely associated with neurotransmitter secretion, neuronal activity, neuronal gene expression, and synaptic remodeling [39‒41]. Dietary-derived molecules processed by gut microbiota may result in formation of metabolites that alter gut permeability, blood-brain barrier function, cause neuroinflammation, vagus nerve activation, neurogenesis, and excitotoxicity [42].

Conditions such as hypertension, obesity, glucose intolerance have been associated with gut microbiota dysregulation [32]. These disturbances in microbiota composition may have several effects on neurons including but not limited to neuroinflammation, excitotoxicity, and synaptic changes as described earlier [39‒42] (Fig. 2). An imbalance in the microbiome has been related to MetS and specific microbial metabolites, such as trimethylamine N-oxide, have been associated with cognitive decline in experimental studies [42, 43]. Investigators have suggested that effects of neuroinflammation and oxidative stress on hippocampus may explain poor memory observed in patients with MetS [30]. Further experiments investigating gut microbiome alterations as an important common factor between cognitive decline and MetS are needed to further elucidate this topic [32].

Probiotics (live microbes) could have anti-inflammatory and anti-oxidative effects, leading to improvement of age-related cognitive decline [32]. Probiotics increase glucagon-like peptide 1 (GLP-1) levels and improve gut permeability [41]. Additionally, they are associated with improvement in conditions such as obesity, hypertension, hypercholesterolemia, and it is proposed they may decrease risk for diabetes [32]. A metabolic dysfunction-associated steatohepatitis model study reported improved cognition with probiotic administration [41].

Liver disease has been associated with lower cognitive performance [2, 44, 45]. Liver plays a role in the peripheral amyloid-b clearance, and potential dysfunction may lead to cortical amyloid-b and tau protein accumulation, while the lack of hepatokines may also contribute to the cognitive decline observed in these patients [44]. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication in people affected by MetS [46]. There is evidence that MASLD is associated with cognitive dysfunction in various cognitive domains such as memory, concentration, general cognition, mental speed, attention, even without the presence of cirrhosis [47]. For example, middle-aged and older patients with MASLD exhibit higher percentage of cognitive decline in a 4-year period [47, 48]. Moreover, even though patients with DM2 alone exhibit cognitive dysfunction, when MASLD develops, they perform significantly worse in domains such as attention, working memory, and processing speed [49].

Radiologic evidence supports the association between MASLD and cognitive impairment by revealing decreased brain volume on MRI in patients with MASLD. This relationship remains stable when adjusting for common demographic factors and cardiometabolic criteria. However, adipose tissue volume and BMI may be confounding this association [47]. MASLD patients with higher fibrosis scores or evidence of inflammation perform worse in various cognitive tests [47].

Systemic inflammation, insulin resistance, vascular dysfunction, gut dysbiosis, and hyperammonemia are some of the proposed mechanisms beneath the association between MASLD and cognitive impairment [47]. Systemic inflammation starting from liver can cause oxidative stress, neuroinflammation, decreased b-amyloid clearance, and eventually Alzheimer-related changes in the human brain [47]. Gut microbiota have also been implicated as a potential factor in this association since they play central role in the gut-brain communication. For example, microbiota changes may contribute to altered intestinal permeability and chronic inflammation. Certain products of their metabolism such ammonia and endotoxins cause neuroinflammation. The overall role that gut microbiota plays in the relationship between MetS and cognitive dysfunction was discussed previously in more detail. Hyperammonemia caused by dysbiosis on top of decreased liver metabolism in MASLD may have detrimental effects on cognition [47].

High ammonia levels have been identified in both MASLD (with and without liver cirrhosis) and dementia [41, 50]. Ammonia can cross the blood-brain barrier and lead to neurotoxicity and poor synaptic plasticity, contributing to memory loss [41]. Moreover, in brains of humans with dementia, ammonia results in worsening memory by increasing GABA levels, disrupting mitochondrial activity and increasing ROS production [41] (Fig. 3).

Interestingly, high ammonia levels have also been described in patients with DM [41]. It is of important to recognize that higher ammonia levels do not directly lead to dementia but indirectly contribute to the progression of dementia via multiple different pathways (dysregulation of b-amyloid processes, modification of GABAergic and glutamatergic neuronal system, microglia activation, triggering inflammatory processes) [51]. However, given the established knowledge that ammonia dysregulation is central to MASLD pathophysiology and leads to inflammation, hepatocyte damage, and CNS dysfunction, it is another factor to consider when investigating mechanisms by which MetS may affect cognition [50].

Circadian syndrome (CircS) is a relatively new entity that was first described by Zimmet et al. [52] and is considered a result of circadian rhythm disruption due to modern lifestyle factors [24, 52]. For the CircS definition, the same cardiometabolic criteria, as in MetS, is used with the addition of sleep disruption and depression. Interestingly, CircS has been found to be a better predictor of cardiovascular disease development [24]. Moreover, recent large studies in China found that CircS had a greater impact on cognition than MetS alone [24, 53]. Global cognition and episodic memory were found to be most significantly affected [24, 53]. Even though there is no strong evidence on the pathophysiology behind this association, circadian rhythm disturbance, sleep deprivation, and poor sleep quality have been implicated in cognitive dysfunction [53]. Investigators support that altered neurotransmitter activity, disturbance of synaptic activity, hippocampal dysfunction, hypoxia-related damage, and even increased amyloid-b concentrations are just some of the effects of low sleep quality in the brain [24]. Moreover, neuropsychiatric problems may arise in the setting of circadian rhythm disruption, and depression by itself is also associated with structural and functional brain damage [24, 53]. As a result, it may be expected that CircS is even more strongly associated with cognitive impairment than MetS alone [24]. Sleep disorders and the presence of psychiatric disease may be a good predictor for cognitive decline in patients that otherwise meet MetS criteria, and addressing these conditions should be strongly considered in the prevention of cognitive impairment.

In summary, MetS is a cluster of metabolic risk factors that has been typically associated with cardiovascular disease, liver disease, and multiple malignancies. There are concerns regarding the association between MetS and cognitive dysfunction. Overall, MetS has been associated with higher risk for MCI and dementia, while patients with MetS exhibit worse performance and decline in at least one of the main cognitive domains. The cardiometabolic risk factors have varying effects on cognition; however, glucose control dysregulation and hyperinsulinemia have the most prominent consequences. The relationship between MetS and cognitive dysfunction may be influenced by several factors. Time of exposure, diet, exercise, age, and education levels influence this relationship. Insulin resistance and inflammation have a central role in MetS – cognitive decline relationship. However, no clear pathophysiologic mechanism has been identified, and more studies are needed to elucidate this relationship. Studies investigating MetS-cognition relationship do not use the same tools to assess cognition and MetS. Future studies should prioritize use of NCEP-ATP III criteria for MetS diagnosis and adopt widely used cognitive assessment tools. Moreover, there may be other factors influencing the relationship between MetS and cognition. For example, gut microbiota dysbiosis observed in people suffering from metabolic conditions may result in production of metabolites that eventually lead to neuroinflammation and neurodegeneration. Chronic liver disease and more specifically MASLD have been associated with cognitive decline. Hyperammonemia that characterizes MASLD has been implicated in this association. Finally, recent studies show that disruption of circadian rhythm, which characterizes modern lifestyle, on top of MetS is a factor that is also associated with cognitive decline, and clinicians should pay attention to that. More studies are needed to elucidate CircS relationship with cognition and establish possible superiority against MetS in predicting cognitive decline.

The authors have no conflicts of interest to declare.

The authors have no financial arrangements or grant support to disclose.

Spyridon Zouridis: literature search/investigation, data collection, and manuscript writing. Ahmed Basel Nasir and Patricia Aspichueta: literature search and manuscript writing. Wing-Kin Syn: conceptualization, review and editing, and supervision.