Dementia is one of the major global health challenges, with almost 50 million people currently living with a diagnosis, and by 2050, this number is expected to increase to 131 million
[1]. Dementia is an “umbrella” term that includes several different neurodegenerative conditions, with AD being the most prevalent and contributing up to 70% of all cases, followed by vascular dementia, which accounts for 15–20% of all cases
[1]. Although the exact etiology of dementia is still unknown, several metabolic disturbances (i.e., prediabetes, T2DM) have been associated with a modest increased risk of cognitive dysfunction across all cognitive domains
[2]. In a meta-analysis of longitudinal studies, a non-significant pooled association between MetS and incident dementia and AD emerged, and MetS was significantly associated with an increased risk of vascular dementia
[3]. Although the mechanisms linking MetS with cognitive impairment are not well understood, the current evidence indicates an increased dementia risk in people with T2DM, prediabetes and MetS, with common characteristics between conditions including impaired glycemic control, abnormal lipidemic profile and visceral adiposity
[4]. All of these conditions are encompassed under the umbrella of adiposity or obesity-induced cognitive impairment. To date, several meta-analyses of observational studies (
Table 1) examined the association between MetS and its components with the onset or progression of cognitive disorders (i.e., mild cognitive impairment, all-cause dementia, vascular dementia, AD), indicating a clear and representative relationship.
1.1. Adiposity and Cognitive Impairment
Accumulating evidence exists regarding the detrimental effect of adiposity on the central nervous system, consequently resulting in cognitive impairment, including in the domains of attention, executive function, decision making and verbal fluency
[15]. In particular, obesity almost doubles the risk of AD
[6], while obesity in midlife predicts a greater risk of all-cause dementia in later life
[11]. Furthermore, visceral adiposity is also associated with insulin resistance, which, in turn, reduces capillary reactivity and cerebral blood flow, which is a marker of optimal neuronal activity
[16]. In contrast, the extent to which overweight and obesity are risk factors for incident dementia seems to differ between midlife and later life
[11], indicating a potential cascade of events related to the chronological onset of obesity
[17]. Nevertheless, one of the major problems is that overweight and obese individuals at various life stages often live with other cardiometabolic co-morbidities that are associated with an increased risk of developing dementia
[11][18]. The primary genetic risk factor for the development of late-onset AD, namely, apolipoprotein E (ApoE), is also associated with an increased risk of developing MetS
[19]. In addition, emerging evidence indicates the importance of obesity-related systemic inflammation
[20]. In particular, adipose tissue releases proinflammatory cytokines, such as interleukin-6 (IL-6), and inflammation-related proteins, such as C-reactive protein (CRP), resulting in low-grade systemic inflammation
[20]. Moreover, inflammation may alter hypothalamic function, and in turn, cognition and mood through dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, influencing monoaminergic systems
[21][22].
1.2. Diabetes, Insulin Resistance and Cognitive Impairment
The developed, and increasingly developing countries, are facing a diabetes epidemic, with 90% of diabetic individuals experiencing T2DM in parallel with obesity
[23]. Indeed, obesity is strongly linked with metabolic inflammation and lipotoxicity, which are two key mechanisms that can promote insulin resistance, the hallmark of T2DM
[24]. Insulin resistance and pancreatic β-cells failure are the drivers of the chronically elevated circulating glucose levels that characterize T2DM. In particular, chronic hyperglycemia and insulin resistance are at the basis of the complications of T2DM, which were thought to affect only the periphery of the human body by promoting neuropathy, nephropathy and vessel damage
[25]. Nonetheless, T2DM also negatively impacts the central nervous system, as indicated by its association with the onset and progression of neurodegenerative diseases
[26]. In a relatively recent meta-analysis of prospective studies, moderate-to-high-quality evidence demonstrated that T2DM and prediabetes were associated with an increased risk of dementia and cognitive impairment, supporting the paradigm that hyperglycemia and defective glycemic control are pivotal for brain and cognitive health
[27]. In support of this, abnormal fasting or impaired glucose tolerance, HbA1c and abnormal fasting insulin levels are associated with a higher risk of dementia
[7]. Furthermore, findings of the National Health and Nutrition Examination Survey (NHANES) revealed that impaired glycemic homeostasis, leading to elevated plasma glucose levels, is one of the components of MetS that is more strongly associated with cognitive decline
[4].
From a mechanistic perspective, the detrimental effects exerted by hyperglycemia are strictly dependent on the neurotoxic effects elicited by high glucose levels
[27]. The brain makes up 2% of a human’s body weight, but despite this, 20% of the body’s glucose requirement is used by the brain
[28]. The high glucose demand of the brain is guaranteed by a glucose uptake system independent of insulin. Indeed, the blood–brain barrier (BBB) and neurons can take up glucose via GLUT-1 and GLUT-3 transporters, respectively, which are both insulin-independent glucose transporters
[29]. While glucose uptake via mechanisms independent of insulin represents a clear advantage to fulfill the brain glucose demand, it also makes neurons more susceptible to glucose neurotoxicity. However, the BBB does not seem to prevent hyperglycemia from affecting the brain, as demonstrated by the increase in glucose levels in the brain extracellular fluid of diabetic animals
[30]. The increase in interstitial glucose levels, in turn, promotes abnormally high levels of glucose into the neurons, thus triggering gluconeurotoxicity
[30]. Glucose is also neurotoxic via different mechanisms, including the polyol pathway, the formation of advanced glycation end products (AGEs), oxidative stress and the activation of mitogen-activated protein kinase (MAP) kinases, which were extensively reviewed elsewhere
[31]. However, hyperglycemia is not the only driver of cognitive impairment in the context of T2DM. In this regard, insulin resistance has also been linked with the onset and progression of neurogenerative diseases
[32]. It cannot be overlooked that besides its metabolic role in the periphery, insulin also acts in the central nervous system to regulate energy balance, glucose metabolism, neuronal function, plasticity, learning and memory
[33]. The importance of the role of insulin in the brain is evidenced by the fact that it can enter the nervous system and regulate its function in light of the broad expression of its cognate receptor throughout the brain, which has been reported in the hypothalamus, as well as areas involved in memory function, such as the hippocampus and the prefrontal cortex
[34]. Furthermore, in order to target the central nervous system, intranasal administration of insulin exerted beneficial effects on cognitive function in healthy adults, as well as individuals affected by mild cognitive impairment or AD
[35]. Thus, in consideration of the fact that the role of insulin in the central nervous system goes well beyond metabolic regulation, it is plausible that defective insulin signaling and insulin resistance may represent a further mechanism that bridges the gap between MetS and cognitive impairment.
Peripheral insulin resistance was associated with cognitive decline
[36]. However, insulin resistance is not limited to peripheral tissues, with impaired insulin signaling being reported to affect the brain, as indicated by a decrease in protein kinase B phosphorylation in a variety of animal and cell models of insulin resistance
[37]. Insulin resistance may represent a better predictor of memory impairment than elevated blood glucose, thereby providing further support to the role of insulin resistance as a key mechanism driving cognitive decline
[38]. Thus, it appears clear that T2DM and AD share common features regarding insulin resistance and impaired brain glucose metabolism, which has led some investigators to refer to this neurodegeneration as type 3 diabetes
[39]. Insulin resistance promotes key pathogenetic features of AD, including increased phosphorylation of tau and accumulation of amyloid β, which further support, also from a mechanistic perspective, the impact of defective brain insulin signaling on cognitive impairment
[37]. Further support to the nexus between insulin resistance, hyperglycemia and cognitive impairment is provided by the ApoE gene. Not only do ApoE ε4 carriers not respond to intranasal insulin treatment, but this ApoE isoform also impairs cerebral glucose metabolism, assessed by fluorodeoxyglucose positron emission tomography scan and insulin signaling in mice
[40].
Thus, impaired glucose metabolism and homeostasis and insulin resistance are at the forefront in linking MetS with cognitive disorders. In light of this, interventions to improve insulin sensitivity and glucose metabolism are emerging and represent promising strategies to improve cognitive function
[41].
1.3. Hypertension and Cognitive Impairment
Effective screening and management of hypertension are identified as a Class I recommendation for preventing cognitive decline
[6]. Elevated blood pressure, especially in midlife, has been associated with the onset and development of dementia and cognitive impairment later in life
[42]. In a meta-analysis of prospective epidemiological studies, moderate-quality evidence indicated that midlife hypertension was related to a 1.19-to-1.55-fold excess risk of cognitive impairment
[43]. Additionally, midlife systolic blood pressure over 130 mmHg was associated with an increased risk of cognitive impairment
[43]. In another recent meta-analysis of twelve randomized controlled clinical trials, lowering blood pressure with antihypertensive agents was significantly associated with a lower risk of incident dementia or cognitive impairment
[44]. Several mechanisms were suggested and potentially grouped into three broad categories: action on the concurrent vascular pathology, action on the vascular component of AD pathophysiology and action on non-vascular targets
[45]. Furthermore, these mechanisms can include targeting blood–brain barrier dysfunction, which contributes to amyloid-related cerebral angiopathies and reduced total brain volumes, impaired cerebral blood flow and delivery of nutrients/oxygen into the brain accompanied with significantly poorer cognitive performance
[46].
1.4. Atherogenic Dyslipidemia and Cognitive Impairment
Low levels of HDL cholesterol (HDL-C) and hypertriglyceridemia are key components of the development of MetS. Dyslipidemia contributes to the development of atherosclerotic lesions, leading to microvascular dysfunction, which has been associated with worse cognitive performance
[47]. Many AD susceptibility
loci, such as the APOE variant carriers identified by genome-wide association studies, are also involved in lipid metabolism
[48]. In a network analysis of lipoprotein profile and its association with cognitive impairment, both increased triglycerides (TGs) and low HDL-C levels were associated with poor self-rated cognitive performance
[49]. The HDL-C and apolipoprotein A-I (ApoA-I) promote the efflux of excess cholesterol via cholesterol transporters, such as the ATP-binding cassette transporter A1 which is involved in the pathogenesis of AD
[50]. Interestingly, increased ApoA-I was shown to be associated with a decreased risk of TD2M in males, but not females, who are more likely to develop AD than males
[51]. Thereby, disturbances in the metabolism of HDL-C may influence cognition and neuronal growth and repair, and mounting evidence indicates that HDL-C modulates cognitive function in aging and age-related neurodegenerative disorders
[47]. The STOP-Dementia cross-sectional study, involving adults over 65 years diagnosed with AD or mild cognitive impairment, revealed a strong relationship between the levels of small-sized HDL particles and mild cognitive impairment
[52]. Furthermore, the role of HDL in the cardiovascular systems has been extensively studied and its cardioprotective roles are well established, where HDL particles can be formed in the systemic circulation and the nervous system. Therefore, HDL particles also play a crucial role in the potential targets for the development of small peptides mimicking the HDL as therapeutics for the treatment of AD
[53]. Hypertriglyceridemia is also linked with neurodegeneration, yet limited studies exist with non-significant results
[9][54]. However, observational studies suggest increased TG levels in the serum of individuals living with AD
[55], in addition to being a shared risk factor between the development of dementia and atherosclerotic CVD
[56].