**1. Introduction**

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Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, re‐ sulting in progressive cognitive dysfunction. The causes of Alzheimer's disease (AD) have not been fully discovered, there are three main hypotheses to explain the phenomenon: a) The deficit of acetylcholine; b) The accumulation of beta-amyloid (Aβ and / or tau protein; and c) Metabolic disorders.

The clinical criteria for diagnosing AD were defined in 1984 by the NINCDS-ADRDA; (Na‐ tional Institute of Neurological and Communicative Disorders and Stroke; Alzheimer's Dis‐ ease and Related Disorders). It states that for the diagnosis of disease is required to prove the existence of chronic and progressive cognitive impairment in adults or elderly patients, without other underlying causes that can explain this phenomenon. However, using this cri‐ terion, it is difficult to differentiate between AD and other causes of deterioration in early stages of the disease.

© 2013 Ortiz 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.

A number of recent research has been related AD with metabolic disorders, particularly hy‐ perglycemia and insulin resistance. The expression of insulin receptors has been demon‐ strated in the central nervous system neurons, preferably in the hippocampus. In these neurons, when insulin binds to its cellular receptor, promotes the activation of intracellular signaling cascades that lead to change in the expression of genes related to synaptic plastici‐ ty processes and enzymes involved in clearing the same insulin and Aβ. These enzymes de‐ grading of insulin promotes the reduction of toxicity due to amyloid in animal models.

**2. Dementia and pathological changes**

ease (AD) is the most common cause of progressive dementia [1].

the relationship between diabetes and AD [5,6].

Dementia is a syndrome that cause cognitive and memory alterations; problems of orienta‐ tion, attention, language and solving problems. Dementia involves a progressive decline in cognition that goes above and beyond the normal changes that come with age due to inju‐ ries or brain diseases. The two most common causes of dementia are AD and vascular de‐ mentia. More than 33% of women and 20% of men aged 65 year or more will develop dementia during their lifetime, and many more develop a milder form of cognitive impair‐ ment. Worldwide, the adult population is rapidly growing; prospective epidemiological studies suggest that there will be an increase of 50% of the total number of people with cog‐ nitive disorders in the next 25 years. Dementia is associated with increased mortality and disability, health care costs they mean a huge expenditure on health systems as well as a sig‐ nificant increase in social and economic responsibilities for caregivers and their families. With a current affection about 10% of the population over the 65 year-old Alzheimer's dis‐

Alzheimer Disease and Metabolism: Role of Cholesterol and Membrane Fluidity

http://dx.doi.org/10.5772/54091

147

AD is a progressive neurological disorder resulting in irreversible loss of neurons, partic‐ ularly in the cortex and hippocampus, accounting for about one third of dementia syn‐ dromes, with a range that varies from 42 to 81% of all dementias. The clinical findings are characterized by progressive loose of memory, loss of: judgment, decision making, physical orientation and language disorders. The diagnosis is based on neurological ex‐ amination and differential diagnosis with other dementias, but the definitive diagnosis is made only by autopsy. The pathological findings at microscopic level are: neuronal loss, gliosis, neurofibrillary tangles, neuritic plaques, Hirano bodies, granulo-vacuolar degener‐ ation of neurons and amyloid angiopathy [2, 3]. A very early change in AD brain is the reduced glucose metabolism [4], and a recent analysis suggests that diabetes plays a role in the acceleration of brain aging. But, although it is known that type 2-diabetes may be associated with an increased risk of dementia, the exact mechanisms and mitigating fac‐ tors still are not completely understood. The public health implications of this phenom‐ enon are enormous. Although initially the association between type 2 diabetes and vascular dementia appeared to be more consistent than the relationship between type 2 diabetes and AD, there are recent studies that have yielded more consistent evidence of

Neuritic plaques, neurofibrillary tangles and other proteins in AD brain are glycosylated [7]. Since people with diabetes have an increased blood glucose level is plausible to sus‐ pect that they have a higher chance of having AD. Animal models of induced diabetes suggest a direct neurodegenerative effect of diabetes; most of these studies show damage in the hippocampus, an area associated with learning and memory, and first structure to be affected by the neurodegeneration of AD disease. A post-mortem study revealed that people with diabetes and ApoE 4 allele, had more neuritic plaques and neurofibrilar tan‐ gles in the hippocampus and cortex, also cerebral amyloid angiopathy, in which the as‐ sociated protein AD disease is deposited on the walls of blood vessels in the brain. It has been shown that those with diabetes have a greater cortical atrophy, independent of

People with neuritic plaques accumulate in brain regions that correspond to brain re‐ gions in healthy people that rise in a metabolic process called aerobic glycolysis. While some regions such as prefrontal and parietal cortex, which is thought to have a role in self-recognition and control tasks, showed high levels of aerobic glycolysis, others such as the cerebellum and the hippocampal formation, believed to affect the control motor and memory, showed low levels. Brain cells use aerobic glycolysis for energy derived quickly from small amounts of glucose while obtaining the mass of its energy through a biochemical process effective to burn glucose. Since aerobic glycolysis may help the brain generate cell constituents, toxic metabolic byproducts manage and regulate programmed cell death; the findings suggest a possible link between brain function that provides ener‐ gy to aerobic glycolysis and the onset of AD.

The causes of the late AD appear to be multifactorial, and cell biology studies point to cho‐ lesterol as a key factor in protein precursor of beta Amyloid (APP) processing and Aβ pro‐ duction. An alteration in cholesterol metabolism is attractive hypotheses, thus the carriers of the Apolipoprotein E4 genes, which is involved in cholesterol metabolism, are at increased genetic risk for Alzheimer's disease. Cholesterol is a component of cell membranes and par‐ ticularly is found in microdomains functionally linked to the proteolytic processing of APP. In sporadic AD, a marked diminution of both membrane phospholipids and cholesterol has been found.

Epidemiological studies indicate that mild hypercholesterolemia may increase the risk of AD and decreased synthesis of cholesterol through statin administration can reduce the de‐ velopment of AD. Moreover, high cellular cholesterol content has been shown to favor the production of Aβ. Genetic studies have suggested links between AD and cholesterol control several genes including cholesterol acceptor ApoE (ε4 polymorphism). Liver X receptors (LRXs) are ligand-activated transcription factors of the nuclear hormone receptor superfami‐ ly LXRs and also are expressed in the brain. LXRs stimulate the expression of genes in‐ volved in cellular cholesterol transport, regulation of lipid content of lipoproteins (apoE, lipoprotein lipase, cholesterol ester transfer protein, and phospholipid transfer protein), me‐ tabolism of fatty acids and triglycerides (sterol regulatory element binding protein 1-c, fatty acid synthase, stearoyl coenzyme A desaturase 1, and acyl coenzyme A carboxylase). Many questions remain, but as a master regulator of cholesterol homeostasis, LXR may be consid‐ ered as a potential molecular target for the treatment of AD.

In summary, numerous studies on the role of cholesterol in AD suggest that high cholesterol is a risk factor for early and late AD development.
