**1. Introduction**

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408 Understanding Alzheimer's Disease

*"I have lost myself"*

*- Auguste Deter, the first patient diagnosed with Alzheimer's Disease, 1906*

**Identification of Alzheimer's Disease** Alois Alzheimer was a German neuropathologist and among the first to identify and describe the hallmarks of what is known today as Alzheimer's disease (AD). In November of 1901, Dr. Alzheimer was presented with 51 year-old Auguste Deter who was suffering from mental incompetence, aphasia, disorientation, paranoia, and unprovoked bursts of anger. Deter's emotional and mental devastation became evident when she confided to Dr. Alzheimer "I have lost myself."

Symptoms similar to Deter's had been observed in patients for years and were considered a natural part of aging. However, it was unusual for such a pointed disease state to occur in someone so young. Over the next four and half years, Deter became increasingly demented, until her death at the age of 55. Upon examination of Deter's brain, Dr. Alzheimer found microscopic strands of protein which he described as "tangled bundles of fibrils" (neurofi‐ brillary tangles) in addition to "miliary foci" (amyloid plaques). In 1906, at the 37th Conference of South-West German Psychiatrists in Tübingen, Alois Alzheimer presented Deter's case as, "a peculiar disease of the cerebral cortex."

To this day both the cause of and treatment for AD remain a mystery. AD is a multifaceted disease of great complexity, however, over 100 years of research has provided clues to its mechanisms. Of particular recent interest is the emerging realization that another rapidly growing disease, type 2 diabetes mellitus (T2DM), is linked to development of AD [1].

This chapter examines the current state of knowledge regarding the association of T2DM to vascular changes in the brain and the implications these changes have in AD development.

© 2013 Aulston et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Other factors that contribute to AD such as insulin resistance and accumulation of the neurotoxic peptide amyloid beta (Aβ) are also examined. It's likely that no central cause of AD exists but rather, the disease represents a breakdown of several critical components involved in the general health and function of the brain.

**Vascular complications associated with type 2 diabetes** It is estimated that approximately 200 million people worldwide have diabetes and by 2025 the number is expected to increase to 333 million [22]. Epidemiological studies have indicated that patients with T2DM have a greater incidence of cardiovascular disease, cerebrovascular disease (CVD), hypertension and renal disease relative to the general population [8, 9]. In addition, a large number of populationbased studies have identified diabetes as a risk factor for dementia [23-25], primarily as a result of CVD [26, 27]. At only 3% of body weight, the brain uses ~20% of the body's oxygen and ~25% of the body's blood glucose [28, 29], demonstrating that it is by far the most metabolically active organ. This oxygen and glucose consumption is constantly required, since brain neurons are obligate aerobic cells and have no other source of energy. The majority of this energy is used to maintain cellular ionic homeostasis, and thus when cerebral blood flow (CBF) ceases, brain function ends within seconds and damage to neurons occurs within minutes [30].

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 411

The vascular complications associated with diabetes can be divided into two classes based on the vascular etiology of their pathology: macrovascular (hypertension, coronary artery disease, atherosclerosis, stroke) and microvascular (neuropathy, retinopathy, nephropathy). Macro‐ vascular complications are those that affect the larger (non-capillary) blood vessels. Statistics show that diabetes increases the risk of stroke and atherosclerosis [31]. Atherosclerosis accounts for 70% of morbidity associated with T2DM [32], while other studies have shown an association between the degree of hyperglycemia and increased risk of myocardial infarction and stroke [33-36]. While macrovascular complications themselves represent important pathological consequences of T2DM, they have also been shown to provide the etiological link

**Link between type 2 diabetes and Alzheimer's disease** AD is an age-related disorder characterized by progressive cognitive decline and dementia. An estimated 5.3 million people in the United States are currently affected and represents the sixth-leading cause of death. Significant evidence has been provided that links T2DM to AD. For example, a comprehensive meta-analysis showed that the aggregate relative risk of AD for people with diabetes was 1.5 (95%-CI 1.2 to 1.8) [37]. Studies have shown that T2DM, impaired fasting glucose and increased islet amyloid deposition are more common in patients with Alzheimer's disease than in control subjects [38, 39]. Unsurprisingly, insulin signaling provides an important mechanistic link

Ischemic CVD caused by T2DM is positively associated with AD through shared pathological mechanisms such as hyperinsulinemia, impaired insulin signaling, oxidative stress, inflam‐ matory mechanisms and advanced glycation end-products (AGEs) [40]. Defective insulin signaling is associated with decreased cognitive ability and development of dementa, includ‐ ing AD [41], rendering signaling neurons more vulnerable to metabolic stress and accelerating neuronal dysfunction [42]. In vitro insulin-stimulated Akt phosphorylation is decreased in hyperinsulinemic conditions in cortical neurons [43]. Finally, all forms of amyloid beta (Aβ) (monomers, oligomers and Aβ-derived diffusible ligands (ADDLs)) can inhibit insulin

signaling by directly binding to the insulin receptor and inhibit insulin signaling [44].

**Mechanisms of macrovascular complications of diabetes** A central pathological mechanism in diabetic-related macrovascular disease is atherosclerosis, which leads to the hardening of

between T2DM and the development of Alzheimer's disease.

between T2DM and AD.

**Epidemiology of AD and T2DM** AD is the most common form of dementia [2] and remains incurable. While the cause of AD remains unknown, several risk factors have been identified that may provide insight into the fundamentals of AD pathogenesis.

T2DM is a known risk factor for AD [1] suggesting that insulin signaling abnormalities play a central role in AD pathology. Moreover, AD brains show decreased insulin levels, decreased activity of insulin receptors and signs of compensatory mechanisms such as increased insulin receptor density [3] indicating AD as "type 3 diabetes" [4, 5].

Loss of insulin signaling in diabetes can occur by either type 1 or type 2 processes. Type 1 diabetes mellitus (T1DM) is characterized as an autoimmune disease that results in the destruction of insulin producing β cells found in the pancreas. In contrast, T2DM is a state of insulin resistance in which insulin levels are normal or elevated but tissues are unresponsive to its effects. While both T1DM and T2DM can lead to cognitive deficits, T2DM poses a greater risk for AD development [6, 7] and as a result the parallels between T2DM and AD are studied more vigorously than T1DM associations. Therefore, the majority of information presented here pertains to type 2 diabetic pathologies.

In addition to insulin resistance, T2DM is associated with the development of vascular dysfunction in the brain [8, 9]. T2DM is a risk factor for microvascular complications as well as macrovascular defects [10] such as stroke [11]. Vascular abnormalities are strongly associ‐ ated with AD [12-16] implying further involvement of T2DM in disease onset.
