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 [31]. In particular, obesity almost doubles the risk of AD [22], while obesity in midlife predicts a greater risk of all-cause dementia in later life [27]. 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 [32]. In contrast, the extent to which overweight and obesity are risk factors for incident dementia seems to differ between midlife and later life [27], indicating a potential cascade of events related to the chronological onset of obesity [33]. 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 [27,34]. 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 [35]. In addition, emerging evidence indicates the importance of obesity-related systemic inflammation [36]. 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 [36]. Moreover, inflammation may alter hypothalamic function, and in turn, cognition and mood through dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, influencing monoaminergic systems [37,38].

The developed, and increasingly developing countries, are facing a diabetes epidemic, with 90% of diabetic individuals experiencing T2DM in parallel with obesity [39]. Indeed, obesity is strongly linked with metabolic inflammation and lipotoxicity, which are two key mechanisms that can promote insulin resistance, the hallmark of T2DM [40]. 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 [41]. Nonetheless, T2DM also negatively impacts the central nervous system, as indicated by its association with the onset and progression of neurodegenerative diseases [42]. 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 [43]. In support of this, abnormal fasting or impaired glucose tolerance, HbA1c and abnormal fasting insulin levels are associated with a higher risk of dementia [23]. 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 [20].

From a mechanistic perspective, the detrimental effects exerted by hyperglycemia are strictly dependent on the neurotoxic effects elicited by high glucose levels [43]. 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 [44]. 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 [45]. 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 [46]. The increase in interstitial glucose levels, in turn, promotes abnormally high levels of glucose into the neurons, thus triggering gluconeurotoxicity [46]. 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 [47]. 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 [48]. 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 [49]. 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 [50]. 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 [51]. 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 [52]. 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 [53]. 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 [54]. 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 [55]. 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 [53]. 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 [56].

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 [57].

Effective screening and management of hypertension are identified as a Class I recommendation for preventing cognitive decline [22]. Elevated blood pressure, especially in midlife, has been associated with the onset and development of dementia and cognitive impairment later in life [58]. 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 [59]. Additionally, midlife systolic blood pressure over 130 mmHg was associated with an increased risk of cognitive impairment [59]. 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 [60]. 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 [61]. 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 [62].

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 [63]. Many AD susceptibility loci, such as the APOE variant carriers identified by genome-wide association studies, are also involved in lipid metabolism [64]. 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 [65]. 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 [66]. 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 [67]. 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 [63]. 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 [68]. 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 [69]. Hypertriglyceridemia is also linked with neurodegeneration, yet limited studies exist with non-significant results [25,70]. However, observational studies suggest increased TG levels in the serum of individuals living with AD [71], in addition to being a shared risk factor between the development of dementia and atherosclerotic CVD [72].

Adherence to the Mediterranean dietary pattern is inversely associated with the risk of developing dementia and cognitive impairment [73]. Findings from large-scale cohort studies and long-term intervention trials support the protective effect of this pattern against several neurodegenerative disorders [74]. Among the largest prospective observational studies are the Singapore Chinese Health Study (16,948 men and women followed for an average of 20 years) [75], the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk, 8009 older individuals with an average of 13 years of follow-up) [76], the EPIC-Spain study (16,169 adults followed for approximately 22 years) [77] and the Coronary Artery Risk Development in Young Adults (CARDIA, with follow-up for up to 20 years) [78]. These studies found that higher adherence to a Mediterranean diet was associated with a significantly lower risk of developing all-cause dementia, AD or mild cognitive impairment.

Similar promising outcomes were also revealed by randomized controlled clinical trials, such as the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) study with a dietary intervention that highly overlapped with the typical Mediterranean diet yet gave more focus to foods suggested as neuroprotective due to the inclusion of nutrient-dense foods, such as green leafy vegetables and berries [79]. Additionally, a sub-analysis from the Prevención con Dieta Mediterránea (PREDIMED) study (PREDIMED-NAVARRA) showed an improvement in cognition in both Mediterranean diet groups compared with the control, suggesting that even in individuals with established MetS and increased cardiometabolic risk, the protective effect of this dietary pattern still exists [80]. The PREDIMED-NAVARRA study also demonstrated better cognitive performance in non-ApoE-ε4 carriers, but non-ApoE-ε4 carriers, in the clock drawing test following the Mediterranean diet intervention [81]. Comprehensive meta-analyses have summarized the results of observational and interventional studies on the associations between the Mediterranean diet and cognitive impairment and concluded that dietary patterns like the Mediterranean diet have protective effects (Table 2), suggesting that higher adherence may be associated with a lower risk of mild cognitive impairment and AD. Another meta-analysis revealed that the Mediterranean diet has a beneficial effect on global cognition in older adults [82].

Several mechanistic studies suggested that the Mediterranean diet prevents telomere shortening, which is associated with a reduced risk of many age-related diseases, including cognitive impairment [97]. Other studies suggest that increased adherence is inversely associated with various AD biomarkers [98] and positively affects brain morphology and function [99]. In addition, there are several meta-analyses that document the role of the Mediterranean diet in controlling MetS and its components [100,101,102,103], which in turn could have a preventive effect against cognition-related disorders.

Although the overall diet can profoundly affect the brain, accumulating evidence suggests that consumption of specific dietary food groups as a part of the overall diet can improve cognitive outcomes. Therefore, several foods, food groups and beverages have been examined regarding their protective effects on cognitive impairment (Table 2).