*4.1. From Metabolic Syndrome to Cognitive Impairment*

Cardio-metabolic risk factors and MS affect cognition and increase the risk of major neurocognitive disorders [98–100]. Speed of processing, attention, and executive functions are the most frequently affected domains [101,102]. Thus, an association is often reported between risk factors, such as hyperlipidemia, T2DM, obesity, hypertension, and physical inactivity, and models of risks of cardiovascular disease (CVD) (e.g., Framingham Risk Score) with the risk of MCI and major neurocognitive disorders (Table 1) [103–106].

Strong evidence of a link between high blood pressure in middle age and poorer cognitive function in old age is available [107,108]. Different prospective studies in older people show that increased blood pressure is associated with worse cognitive function [109]. The risk of cognitive impairment can increase up to 2.8 times [110]. In older women, risks may increase by up to 20% [111]. Similar results were reported in individuals from Hispanic [112], Swedish [113], Asian [114], and North American communities [115,116].

Obesity, defined by a high abdominal circumference or a body mass index (BMI) ≥ 30, is also associated with poor cognitive function [117,118]. Individuals with high BMI during middle age show low scores among various cognitive tests [119]. Further, long-term obesity is linked to lower cognitive performance and an increased risk of neurocognitive impairment in older people [120–122].

Several epidemiological studies and meta-analyses provide evidence for an effect of hyperlipidemia, hypertriacylglycerolemia, and HDL-C levels on cognitive performance in individuals with and without major neurocognitive disorders. Elevated LDL-C levels are correlated with the degree of cognitive impairment [123] and decreased episodic memory (ECM) [124]. Further, hypertriacylglycerolemia is associated with low scores in verbal tests [124,125]. Low concentrations of this lipoprotein are associated with poor and decreased memory in middle-aged adults [126], while in older people, low levels are associated with major neurocognitive disorders [127]. In contrast, improvement in cognitive test performance is reported for subjects over 75 years old with high HDL-C [128,129], which is also associated with a significant decrease in the appearance of major neurocognitive disorders [130].

Hyperinsulinemia, glucose intolerance, and T2DM are other cardio-metabolic risk factors that recently have been associated with cognitive impairment and different major neurocognitive disorders [131]. Hyperinsulinemia and impaired glucose tolerance, both indicators of a prediabetic state and an increased risk of developing DM, are associated with cognitive dysfunction and an increased risk of developing MCI [132–135]. These premorbid states are associated with reduced long-term memory scores [136] and impaired verbal fluency [137]. Lower performance on psychomotor and memory tests is observed in diabetic individuals [138]. These lower scores correlate with an increased risk of developing cognitive impairment and MCI [139–143].

Several studies associate different elements of MS with cognitive functions. However, few studies of MS as a clinical entity and its relationship with MCI or its progression to major neurocognitive disorders are available. Roberts et al. reported a cross-sectional study in 1969 of 70 89-year-old individuals. Participants with MS showed non-amnestic MCI (naMCI) when accompanied by elevated C-reactive protein (CRP). The combination of inflammation and MS might be linked to specific subtypes of MCI [144]. Yaffe et al. conducted a longitudinal, multicenter study with 4895 women with an average age of 66.2 years. MS was associated with an increased risk of developing cognitive impairment in older women. Risk increased by an age-adjusted 23% for each increment in the number of MS components [145]. Similar findings were reported by Pal et al. [146] and Atti et al. [147], who concluded that MS is associated with an increased incidence of major neurocognitive disorders and an increased risk of progression from MCI to such disorders, respectively.


**Table 1.** Effects of components of MS on cognitive function, the risk of MCI, and major neurocognitive disorders.


**Table 1.** *Cont*.

Abbreviations: MS: metabolic syndrome; MCI: mild cognitive impairment; BP: blood pressure; CAMCOG: Cambridge Cognitive Examination; MMSE: Mini-Mental State Examination; CV: coefficient of variation; BMI: body mass index; OR: odds ratio; HR: hazard ratio; CI: confidence interval; AD: Alzheimer's disease; HDL-c: high-density lipoprotein; DM: diabetes mellitus.

> The impact of MS on cognitive function is not limited to adults. There is also evidence that suggests that MS components may be detrimental in younger populations. The presence of T2DM, obesity, and hypertension in children and adolescents is associated with poorer performance in overall functioning, and declines in executive function, memory, attention, and intelligence quotient (IQ) [148–152].

> Cardiovascular and metabolic risk factors are modifiable and their timely identification and consequent management could prevent MCI or its progression to major neurocognitive disorders [101]. Thus, lifestyle changes, including increased physical activity and implementation of healthy diets, and antihypertensive, hypolipidemic, and insulin-sensitizing drugs are important considerations for the management of premorbid state characteristics of MS (Table 2) [153].

> Changes in lifestyle and physical activity positively impact cognitive function. [154,155]. Physical activity is associated with better scores on tests of executive function, processing speed, and improvement in global cognitive function. These benefits were found both in healthy older subjects and in older subjects with MCI or major neurocognitive disorders [156–159]. More studies to elucidate types of exercise, times, and intensity needed to cause a positive impact on cognition are necessary; still, 150 min of physical activity per week is proposed to improve the brain health of individuals with MCI [160].

> Better results are obtained if physical activity is combined with a healthy diet. Supplementation with B-vitamins, folic acid, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and flavonoids is associated with improved cognitive performance, particularly memory, in subjects with MCI [161]. Similarly, both cognitively normal individuals and those with MCI are reported to be at less risk of developing MCI or AD if they maintain high adherence to a Mediterranean diet [162]. Similar results are associated with Mediterranean-DASH diets [163], low-carbohydrate diets (keto-diet) [164], and fish PUFA diets [165].

Additionally, a causal relationship between antihypertensive drugs and improved cognitive function is supported by available evidence. Antihypertensive drugs, especially calcium channel blockers and renin–angiotensin system blockers, have a protective effect on cognitive decline and decrease the risk of AD and neurocognitive vascular disorders in older people [166]. Similarly, treatment with antihypertensive drugs reduces the risk of major neurocognitive disorders by 9% and shows improvement in all cognitive domains, except language [167]. Longitudinal studies that included older individuals without major neurocognitive disorders who were undergoing antihypertensive therapy produced supporting results [110,168].

Controlling glycemic concentrations and increasing peripheral insulin sensitivity are strategies that might positively affect cognitive function [146]. A recent meta-analysis showed that treatment with metformin or sulfonylureas is associated with a significant decrease in cognitive impairment in patients with T2DM. In contrast, the use of insulin aggravated the dysfunction [169]. Studies of metformin as monotherapy [170], or combined with vildagliptin [171], on the participants' cognitive function produced similar results. However, other studies show no association between the use of antidiabetic drugs and improvement in cognitive function [172,173]. One study linked the use of such drugs to the diagnosis of MCI [174].

Finally, unlike antihypertensive and antidiabetic drugs, hypolipidemics, such as statins, do not affect the risk of progression to MCI or major neurocognitive disorders of any kind [175,176]. Indeed, several clinical and epidemiological studies report no significant association between statin use and reduced cognitive impairment [177–180].

**Table 2.** Association between treatment of MS elements and MCI improvement.



**Table 2.** *Cont*.

Abbreviations: MS: metabolic syndrome; MCI: mild cognitive impairment; SMD: standardized mean difference scores; PUFAs: polyunsaturated fatty acids; MMSE: Mini-Mental State Examination; CV: coefficient of variation; OR: odds ratio; RR: relative risk; HR: hazard ratio; CI: confidence interval; DSST: Digit Symbol Substitution Test.

#### *4.2. Exploring the Reverse Relationship—From Cognitive Disorder to Metabolic Syndrome*

Epidemiological studies suggest the inverse relationship. MCI has been assessed as a contributor to the development of MS (Table 3). In a cross-sectional study of 3312 male and female participants aged 70 years and older in Japan, a higher prevalence of MS was observed in subjects with naMCI than in those with normal cognition. Moreover, women with naMCI had high blood pressure and high glucose levels more often, while men with naMCI showed only a higher frequency of high glucose levels compared with the control group. However, a causal relationship between the two could not be determined from this cross-sectional study [181]. Clinical evidence is still scarce and has focused more on specific components of MS, such as insulin/glucose alterations and T2DM, than on MS as an entity.

Alterations in insulin signaling have been reported in postmortem studies in brains from individuals with AD [182,183], as well as in patients with AD in clinical studies of plasma hyperinsulinemia and reductions in insulin levels in the CSF. These changes worsen as the disease progresses [184]. Animal models produce similar results [88,185]. Accordingly, Janson et al. used the Mayo Clinic Alzheimer's Disease Patient Registry to show a higher incidence of both T2DM and IR in 80% of AD patients. A greater increase in fasting plasma glucose (FPG) with age compared with the control group was also observed. AD patients might thus be at greater risk of developing a diabetic phenotype and suffering from T2DM [186].

Similarly, a longitudinal study using data from the Lothian Birth Cohort of 1936 (LBC1936) examined parameters, such as cognitive changes and glucose levels. This cohort consists of 1091 initially healthy individuals born in 1936. Individuals were assessed using glycosylated hemoglobin (HbA1c) data for four ages—70, 73, 76, and 79 years. Lower cognitive function at 70 years was associated with increased HbA1c in the following decade. Cognitive dysfunction is thus negatively correlated with increases in HbA1c. Maintaining high cognitive function could be a protective factor for the development of hyperglycemia and T2DM [187].

Likewise, Peng et al. initially conducted a cross-sectional study in 2126 participants, including 1063 patients recently diagnosed with T2DM and 1063 patients with standard glucose tolerance. Individuals with higher plasma concentrations of both Aβ40 and Aβ42 were more likely to have T2DM compared to subjects with the lowest concentrations [188]. In a follow-up study, the authors examined Tongii-Ezhou Cohort (TJEZ) data prospectively. One hundred and twenty-one individuals with T2DM and 242 healthy individuals were

included. The same association was found, where the probability of T2DM was higher with higher plasma concentrations of Aβ, 3.79 (95% CI 1.81–7.94) for Aβ40 and 2.88 (95% CI 1.44–5.75) for Aβ42. The authors conclude that a positive association exists between Aβ and the risk of acquiring T2DM [188].

**Table 3.** Effect of cognitive dysfunction and suffering from MS or MS components.


Abbreviations: T2DM: diabetes mellitus type 2; HbA1c: glycated hemoglobin; FPG: fasting plasmatic glucose; IFG impaired fasting glucose; MCI: mild cognitive impairment; naMCI: non-amnestic mild cognitive impairment; Aβ: amyloid-beta; OR: odds ratio; CI: confidence interval.

> These findings imply that therapeutic intervention aimed at MCI, especially AD, could be beneficial for treating MS and its components (Table 4). A drug approved for the treatment of moderate-to-severe AD is memantine, an NMDA receptor antagonist that reduces the accumulation of Aβ in AD patients [189]. Ettcheto et al. analyzed the effects of memantine in rats with model AD that were fed a high-fat diet. After 12 weeks of treatment with 30 mg/kg memantine, improvement of peripheral metabolic parameters, such as IR, was observed [190].

> Similarly, Ahmed et al. investigated piracetam and memantine in the treatment of T2DM in 120 individuals. Piracetam is used to improve memory and brain function. Diabetic patients with AD treated with either drug showed a significant reduction in diabetic markers (GPA, HbA1c%, and insulin levels) compared to a symptomatic control group. Thus, agents used to treat MCI demonstrate a therapeutic potential for the treatment of metabolic disorder [191].

> Another therapeutic strategy is based on reducing the activity of enzymes that promote the formation of Aβ, such as BACE1. The metabolic role of BACE1 is not fully understood, though loss of BACE1 in transgenic rats leads to increased sensitivity to insulin and

decreased body weight [192]. Its mechanisms of action may involve leptin signaling and thermogenesis [95]. These results were extrapolated in a randomized clinical trial (RCT). Patients with AD treated with lanabecestat, a BACE1 inhibitor, showed greater weight loss than a placebo group after 104 weeks of treatment [193].

Additionally, immunotherapy against Aβ is used to improve insulin sensitivity and plasma glucose levels. Zhang et al. used an APP/PS1 EA rat model with increased plasma levels of Aβ40/42. Animals exhibited altered glucose/insulin tolerance and liver insulin signaling. After nine months of intraperitoneal injections of antibodies against Aβ, an improvement was observed in insulin sensitivity. Hepatic signaling of JAK2/STAT3/SOCS-1 compared to the control group was concurrently attenuated. Thus, neutralization of Aβ attenuates hyperglycemia and IR in vivo [194].

**Table 4.** Summary of preclinical and clinical studies exploring treatment of SM with anti-Alzheimer's drugs.


Abbreviations: MEM: memantin; AD: Alzheimer's disease; HFD: high-fat diet; Aβ: amyloid-beta; RCT: randomized clinical trial; FPG: fasting plasmatic glucose; HbA1c: glycated hemoglobin.

> Numerous epidemiological and clinical studies and meta-analyses provide evidence that MS and its components have a substantial impact on the development of MCI. However, the inverse relationship, where MCI contributes to MS risk, is feasible, though some studies report the lack of association between these clinical entities [195–198]. A causal relationship between MS and MCI has yet to be conclusively identified.
