**8.1 Amyloid formation is the pathological hallmark of T2D and AD**

The incidence of both AD and T2D is increasing at an alarming rate at present and has become a major public health concern in many industrialized countries [73]. Many epidemiological studies have shown that diabetic individuals have a significantly higher risk of developing AD [74]. Recently, it has become increasingly recognized that there is an overlap between the pathology of AD and vascular dementia and cerebrovascular dysfunction plays a role not only in vascular dementia but also in AD [75]. Nevertheless, clinical observations suggest that the association is independent of vascular factors [76], which raises the possibility that diabetic conditions such as insulin resistance and hyperglycemia may affect the fundamental pathogenesis of AD. Many neuronal functions are affected by changes in the insulin signaling pathway; therefore diabetes mellitus may have an important role in the progression of AD ([77]; see **Figure 2**).

Another possible mechanism that has been involved is the **amyloid deposition** in islets composed primarily of islet amyloid polypeptide (IAPP or amylin) that is a common feature in T2D. IAPP amyloid deposition has been correlated with disease severity, reduced β-cell mass, the development of hyperglycemia, and islet inflammation. Similarly, Aβ plays a central role in synaptic dysfunction and in the cognitive deficiencies associated with AD pathogenesis [78]. Evidences from clinical and animal studies associate the pancreatic amyloid, amylin in mediating neuronal loss in AD, suggesting its role as a potential link between AD and T2D pathogenesis [79–81]. The presence of amyloid deposits in pancreas and brain has been demonstrated in patients with T2D, which can serve as seed to increase the aggregation of these deposits. This suggests that pancreatic IAPP can potentiate amyloid beta misfolding in patients with AD [81]. Previously, de la Monte and colleges, 2008, reported that IAPP enters the brain, augments Aβ misfolding, and associates with Aβ plaques, and plasma levels correlate with AD diagnosis [82]. Interestingly, amylin has been identified in human cerebrospinal fluid and brains of diabetic patients with vascular dementia or AD and nondiabetic patients with AD. Furthermore, co-localization of amylin and Aβ deposits was also observed in postmortem human brains [81]. Likewise, amylin deposits were observed in the temporal lobe gray matter in diabetic patients [79]. Therefore, the co-existence of Aβ and amylin in the brain suggests the potential ability of amylin to infiltrate the brain and induce amyloid deposition in the brain [81].
