**6. Role of dietary lipids in Alzheimer disease**

Recent theories suggests that there would be an interaction between genetic predisposition and environmental factors that lead to cell death by amyloid toxicity or disruption of tau protein. Dietary lipids could be a determining factor in the difference in risk between devel‐ oped and underdeveloped countries. Dietary lipids could be the primary risk factor in lateonset sporadic AD (LO-SAT). The critical factors seem to be the ratios of polyunsaturated fatty acids (PUFAs) to monounsaturated (MUFA), saturated fatty acids (SFA) to essential fatty acids (EFAs). These contents are modified by the APOE4 genotype [105].

and the degree of saturation of membrane lipids and fluidity affects its function. The apoE4 genotype may influence the risk of AD, as it is unable to protect that transports

Alzheimer Disease and Metabolism: Role of Cholesterol and Membrane Fluidity

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

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**Figure 7.** Cellular changes induced by lipid oxidation linked to dietary lipids. The change in dietary intake of lipids causing a low PUFA/MUFA (Polyunsaturated Fatty Acid/Monounsaturated Fatty Acids) ratio, which finally altered syn‐

The principal constituents of mammalian cell membranes are phospholipids, the most abundant of which is phosphatidylcholine (PC). PC biosynthesis is initiated by the phos‐ phorylation of choline to form phosphocholine, which then combines with cytidine tri‐ phosphate (CTP) to form 5'-cytidine diphosphocholine (CDP-choline); this compound then reacts with diacylglycerol (DAG) to produce PC [110]. The rate at which cells form PC is affected by the availability of its precursors. Thus, uridine or cytidine increase CTP levels [111]; availability of CTP levels in turn can be rate-limiting in the syntheses of CDP-choline [112] and PC [113]; and DAG levels can control the conversion of CDP-chol‐ ine to PC [114]. AD is also associated with abnormal metabolism of membrane phospho‐

lipids from oxidation [109].

aptic connections and neuron collapse [127].

**7. Membrane phospholipid metabolism**

Oxidation of neuronal lipid membranes could be the initiating event in the cascade of synergistic processes with subsequent expression of Aβ and helical filaments of hyper‐ phosphorylated tau protein. PUFAs are important in modulating the inflammatory bal‐ ance/systemic anti-inflammatory eicosanoids and fluidity and membrane function. Proinflammatory eicosanoids are derived from arachidonic acid (AA). The anti-inflamma‐ tory eicosanoids are derived from the via the n-3 EFA through DHA) and EPA. EFAs cannot be synthesized by animals and must be obtained from food. A diet rich in linole‐ ic acid promotes proinflammatory state, while a diet rich in linolenic acid promotes in‐ flammatory components. When lipids are exposed to free radicals begin an autoperoxidative process. This process is perpetual and changes the composition and rate of membrane lipids with loss of PUFA compared with MUFA and SFA. This causes the membrane to become less fluid and affecting the function of components, as well as of intracellular organelles and the vascular endothelium [106]. This seems to be the ini‐ tial process of the cascade that culminates in neuronal death and neuropathological se‐ quelae associated with LO-SAT. Antioxidant vitamins and vegetables may reduce the risk of AD. High levels of blood lipids are associated with atherosclerosis and diabetes, both risk factors for EA indirect. Recently it was found that the increase in LDL choles‐ terol, along with APOE epsilon4 genotype is associated with increased risk of AD [107].

The oxidative state of lipid membranes can have effects on neurons, at three levels:a) vascu‐ lar;b) endothelial cell membrane; and c) membrane organelles.At the level of cellular mem‐ branes lipid oxidation accelerates the aggregation of amyloid which consequently decreases membrane fluidity. This also is observed with decreases of the content of MUFA and PUFA esterified to phospholipid. Interestingly, these changes are seen in brain regions affected in AD, especially at the hippocampus. The decrease of the membrane fluidity affects the syn‐ aptic connections [108]. The EA may be preventable and treatable and possibly reversible to some extent, if the proposed hypothesis is correct. The changes in the fat composition of the diet are reflected in plasma lipids and phospholipids in the membrane of red blood cells, likewise in the neural cell membranes, especially in areas of rapid lipid turnover. A diet low of n-6 PUFA and MUFA, and an adequate amount of n-3 PUFA, but not too caloric, with antioxidants should protect neuronal damage, lipid oxidation and the inflammatory cascade and amyloid deposition.

Lipid lowering agents appear to have a protective effect, although studies are not conclu‐ sive. Statins decrease the oxidizability of LDL, with decreased levels of oxygen reactive spe‐ cies, anti-inflammatory effects and improve endothelial dysfunction, also increased alphasecretase activity. Increase the synthesis of LDL receptors, with decreased circulating level and reduced production of PPA.

The histological changes seen in the initial stages of AD confirmed that membrane lipids and inflammation are involved in the disease (Figure 7). AGE n-3/n-6 rate has a major impact on the balance of eicosanoid metabolism inflammatory and anti-inflammatory, and the degree of saturation of membrane lipids and fluidity affects its function. The apoE4 genotype may influence the risk of AD, as it is unable to protect that transports lipids from oxidation [109].

**Figure 7.** Cellular changes induced by lipid oxidation linked to dietary lipids. The change in dietary intake of lipids causing a low PUFA/MUFA (Polyunsaturated Fatty Acid/Monounsaturated Fatty Acids) ratio, which finally altered syn‐ aptic connections and neuron collapse [127].
