**6. Diabetes mellitus as a risk factor for dementias**

Dementia is a complex disorder of multifactorial etiology that results in alterations in health status changes in lifestyle. It is important to identify the risk factors, at an early age, to prevent this disease. There are several factors related to dementia such as age [28], ethnic group [29], gender [30], genetic factors [31], physical activity [32], smoking, alcoholism [33], education level [34], environmental factors, and obesity [35, 36]. In addition, in the last decade, DM has been associated as a risk factor for dementia, especially DM2, which is also related to obesity.

Damage to cognitive functions has been observed in patients with DM2 compared to healthy patients [37, 38]. Individuals with DM2 present alterations in their attention capacity, execution, processing speed, work memory, and verbal memory [39, 40]. Studies report a reduction of the gray matter in the frontotemporal cortex, as well as the decrease in glucose metabolism in patients with alterations in executive and memory functions [41], but it also has been associated to a white matter reduction [38]. On the other hand, the damages in verbal memory correlate with the integrity of the parahippocampal gyrus [42]. In other words, DM2 represents an important risk factor for dementia. Interestingly, in the five main countries with a high DM prevalence (see **Table 2**), there is also a significant prevalence of dementia (**Figure 1**).

DM2 is the most common type of diabetes in which autoimmune antibodies appear to be the cause. In this type of diabetes, insulin resistance is observed, which limits the ability to respond to hormones, both endogenous and exogenous [43]. In some cases, insulin resistance is a result of a lower number or a mutation of insulin receptors (IR). These receptors are expressed in the central nervous system (CNS), in the hypothalamus, olfactory bulb, cerebral cortex, cerebellum, and hippocampus [44–46]. Insulin can cross the blood-brain barrier and reach its target, generating anorexic effects by activating the satiety center. This happens because insulin and the insulin-like growth factor-1 (IGF-1) activate PI3K causing the opening of ATP-dependent potassium channels (ChK\* ATP), thus hyperpolarizing the neuron which causes it to disrupt its activity, and thus, it stimulates the secretion of the

#### **Figure 1.**

*Dementia prevalence in the five countries with the highest diabetes mellitus prevalence in 2017. DM, diabetes mellitus (thousands); Dem, dementia (for every 1000).*

#### **Figure 2.**

*Pathway of insulin/IGF-1/PI3K/AKT/GSK3β in respect to the neuronal function and its effect on satiety. Normally, this pathway of insulin/IGF-1 begins when it activates IR and it phosphorylates to begin the pathway for PI3K. Once PKD activates AKT, it will inhibit the activity of GSK3β by phosphorylating in Ser9, which is associated to neuronal survival. On another note, PI3K provokes the opening of potassium canals, via PIP2, hyperpolarizing the neuron which is what conducts the activation of the satiety center. When there is no suitable recognition of insulin, GSK3β will not inhibit; therefore, it will act upon proteins [tau, amyloid-β (Aβ) y α-synuclein (α-syn)] related to the formation of aggregates [neurofibrillary tangles (NFT), amyloid plaques, and Lewy bodies (LB), respectively] which lead to neuronal death and are histopathological characteristics of diseases such as AD and PD. Also, the opening of potassium canals will not be taken care of, inhibiting the satiety (in the presence of insulin, back arrows; lack of insulin, red arrows).*

**217**

*Diabetes Mellitus and Amyloid Beta Protein Pathology in Dementia*

corticotropin-releasing hormone (CRH), which is anorexigenic and inhibits the secretion of neuropeptide Y, which is orexigenic. As mentioned above, insulin activates the PI3K/AKT/GSK3β pathway, where GSK3β is phosphorylated in Ser9 (GSK3β-pSer9) by means of AKT; being phosphorylated at this site inactivates it, resulting in neuronal survival. However, when there is insulin resistance as in the case of DM2 or there is no insulin production (DM1), this pathway does not activate; therefore GSK3β will not be inhibited and will act upon proteins involved in neuronal death such as tau, amyloid-β, and α-synuclein. These proteins will form intracellular (tau) and extracellular (tau, amyloid-β, and α-synuclein) deposits, which are histopathological features (neurofibrillary tangles, plaques, and Lewy bodies) of dementias such as AD and PD (**Figure 2**). Neuronal death caused by the

lack of insulin is one of the reasons why DM is a risk factor for dementia.

**7. Diabetes mellitus and amyloid-β protein pathology in Parkinson's** 

Clinically, Parkinson's disease is defined as a progressive disorder characterized by resting tremor, rigidity, and bradykinesia; however, there may be other manifestations less constant such as postural instability, propulsive gait, dysphagia, autonomic disorders, sebaceous sweating, salivation, and deteriorating superior functions that can lead up to dementia. This disease was described in 1817 by James Parkinson, who described the deficiency of dopamine in the brain of his patients in late 1950 and also described the treatment of this disease with L-dopa in the 1960s. Parkinson's disease is the second most frequent neurodegenerative disorder. It is a motor disease related with the disorder of the basal ganglia specifically via nigrostriatal which is formed by the axons of the dopaminergic neurons of the substance compact nigra which innervate the corpus striatum. This structure is considered the main target of dopaminergic innervation due to the high density of axons it receives and its large size. The main symptoms of Parkinson's disease are caused by the degeneration of dopaminergic neurons via nigrostriatal [47, 48]. A pathological hallmark of Parkinson's disease is the Lewy bodies (LB), eosinophilic inclusions of α-synuclein (α-syn) located in the neuronal soma especially in nigra substance [49]. Besides the (LB) there can be deposits of the protein tau (MNF) and of β-amyloid (plaques). There is existing evidence that α-syn, tau and Aβ act in a synergistic way in the pathology of AD and PD [50, 51] accelerating the aggregation of each [52]. The presence of tau and Aβ was found in patients with PD, and the cognitive function was lower than healthy patients' [53]. It has also been demonstrated that when these three proteins are found in high concentrations, as in PD, it generates changes in CFS tau levels [54], and if these patients are obese as well, they present insulin resistance [55, 56] even though they do not suffer from DM. These patients have deficits of cognitive functions. It is possible that the resistance to insulin accelerates the demential process in patients with PD, and it can lead to more serious motor symptoms. As described before, insulin/IGF-1 activates the route PI3K/AKT/GSK3β, which, besides being involved in the glucose metabolism and the ingestion of food, also plays an important role in the learning and memory process associated with longterm potential (LTP) in the hippocampus [57]. Apparently, insulin stabilizes the production of dopamine and decreases the alterations in movement in a PD model [58–61]. When insulin acts over IR in a suitable way, the result is neuronal survival; however, the lack of insulin provokes that the GSK3β will not be inactivated (when it is phosphorylated in Ser9 by AKT), which leads to the favoring of the formation of MNF, LB, and amyloid plaques (see **Figure 2**). These pathological structures are found frequently coexisting in the hippocampus and cerebral cortex in patients

*DOI: http://dx.doi.org/10.5772/intechopen.84473*

**disease**

#### *Diabetes Mellitus and Amyloid Beta Protein Pathology in Dementia DOI: http://dx.doi.org/10.5772/intechopen.84473*

*Amyloid Diseases*

**216**

**Figure 2.**

*Pathway of insulin/IGF-1/PI3K/AKT/GSK3β in respect to the neuronal function and its effect on satiety. Normally, this pathway of insulin/IGF-1 begins when it activates IR and it phosphorylates to begin the pathway for PI3K. Once PKD activates AKT, it will inhibit the activity of GSK3β by phosphorylating in Ser9, which is associated to neuronal survival. On another note, PI3K provokes the opening of potassium canals, via PIP2, hyperpolarizing the neuron which is what conducts the activation of the satiety center. When there is no suitable recognition of insulin, GSK3β will not inhibit; therefore, it will act upon proteins [tau, amyloid-β (Aβ) y α-synuclein (α-syn)] related to the formation of aggregates [neurofibrillary tangles (NFT), amyloid plaques, and Lewy bodies (LB), respectively] which lead to neuronal death and are histopathological characteristics of diseases such as AD and PD. Also, the opening of potassium canals will not be taken care of,* 

*inhibiting the satiety (in the presence of insulin, back arrows; lack of insulin, red arrows).*

corticotropin-releasing hormone (CRH), which is anorexigenic and inhibits the secretion of neuropeptide Y, which is orexigenic. As mentioned above, insulin activates the PI3K/AKT/GSK3β pathway, where GSK3β is phosphorylated in Ser9 (GSK3β-pSer9) by means of AKT; being phosphorylated at this site inactivates it, resulting in neuronal survival. However, when there is insulin resistance as in the case of DM2 or there is no insulin production (DM1), this pathway does not activate; therefore GSK3β will not be inhibited and will act upon proteins involved in neuronal death such as tau, amyloid-β, and α-synuclein. These proteins will form intracellular (tau) and extracellular (tau, amyloid-β, and α-synuclein) deposits, which are histopathological features (neurofibrillary tangles, plaques, and Lewy bodies) of dementias such as AD and PD (**Figure 2**). Neuronal death caused by the lack of insulin is one of the reasons why DM is a risk factor for dementia.
