Apolipoprotein E ApoE

One of the most likely risk factors for AzD is the patient s genotype for apolipoprotein E (ApoE), which is believed normally to be involved in neuronal repair and growth, but is also found in plaques and tangles. Three distinct forms of ApoE, E2, E3 and E4 are encoded on chromosome 19 but it is the ApoE, E4 allele that occurs at a much higher frequency in late-onset AzD patients (50%) compared with controls (16%) and binds to and possibly increases the formation of )S-amyloid. Many early-onset cases... 

The genetic basis for the more common late-onset AD appears more complex. Genetic susceptibility is more sporadic and it may be more dependent on environmental factors.9 The apolipoprotein E (apo E) gene on chromosome 19 has been identified as a strong risk factor for late-onset AD. There are three variants of apo E however, carriers of two or more of the apo E4 allele have an earlier onset of AD (approximately 6 years earlier) compared with non-carriers.9 Only 50% of AD patients have the apo E4 allele, thus indicating it is only a susceptibility marker. 

Browning, PJ, Roberts, DD, Zabrenetzky, V, Bryant, J, Kaplan, M, Washington, RH, Panet, A, Gallo, RC, and Vogel, T, 1994. Apolipoprotein E (ApoE), a novel heparin-binding protein inhibits the development of Kaposi s sarcoma-like lesions in BALB/c nu/nu mice. J Exp Med 180, 1949-1954. 

In 1993/1994 a series of publications caused a stir in the AD research community, since for the first time they linked a specific neuropathological process in late-onset AD to a genetic marker. Researchers looking at the composition of plaques found that the protein apolipoprotein E (ApoE) was associated with p-amyloid in the cerebrospinal fluid (CSF) of AD patients (Strittmatter et al., 1993). The gene for ApoE is on the same human chromosome (number 19) which was a risk factor in some AD pedigrees. The gene for ApoE comes in three versions (alleles) Apo s2, Apo s3 and, most importantly, Apo s4 these result in three slightly different variants of the protein. Humans carry two versions of the allele and so can have none, one or two of any of the versions of the Apo... 

Apolipoprotein E (ApoE) A protein involved in cholesterol transport that has three major isoforms, one of which, ApoE4, significantly increases the risk of developing Alzheimer s disease. 

Apolipoprotein E (APOE) Cholinesterase inhibitor (Tacrine) Susceptibility to Alzheimer s disease, increased by the epsilon-4 allele, and decreased by epsilon-2 allele (91)... 

Gong, J.-S.,Kobayashi, M.,Hayashi,H. etal. Apolipoprotein E (apoE) isoform-dependent lipid release from astrocytes prepared from human apoE3 and apoE4 knock-in mice. /. Biol. Chem. 277 29919-29926, 2002. 

In addition to the frequency considerations attendant to the examination of polymorphisms or haplotypes, one must also consider the impact of possible differences in the magnitude of effects of any putative loci. The magnitude of any effects is denoted as "scale" effects based on the notion from quantitative genetics that there will be a displacement from the overall population mean for a trait that is dependent on genotype. To illustrate the effects of scale and frequency, consider two well-known examples of genetic effects. These are the effect of the apolipoprotein E (apo E) polymorphism on cholesterol levels and the impact of the familial hypercholesterolemia polymorphism on cholesterol levels. 

Fig. 10.5 Apolipoprotein E (APOE)-relsled serum levels of APOE, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density hpoprotein (LDL) cholesterol, amyloid- 3 peptide (1 2), and histamine in Alzheimer s disease. (Adapted from refs. 12,59, and 289.)...

Fig. 10.7 Brain mapping activity (theta band) according to Global Deterioration Stage (GDS) staging (cognitive deterioration) and apolipoprotein E (APOE) genotype in Alzheimer s disease. (From refs. 19 and 20.)...

Fig. 10.14 Multifactorial therapy in Alzheimer s disease (AD). Apolipoprotein E APOE)-ve aieA therapeutic response. (Adapted from refs. 13-16 aaA 18-20.)...

Fig. 10.16 Interaction of cytochrome P450 (CYP) 2D6 and apolipoprotein E (APOE) in the pharmacogenetics of Alzheimer s disease...

Harris, J.D., Graham, I.R., Schepelmann, S., et al. (2002) Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation (E1-, E3-, polymerase-) adenovirus vector expressing human apoE. Hum. Mol. Genet., 11, 43-58. 

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

Panza F, Solfrizzi V, Colacicco AM, Basile AM, D Introno A, Capurso C, Sabba M, Capurso S, Capurso A. Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer s disease patients and centenarians. Neuroreport 2003 14 605-608. 

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