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Apolipoprotein E (ApoE)
Determination of the ApoE risk-alleles
e2, e3 and e4 in the gene for Alzheimer's disease and familial hyperlipoproteinaemia
RDB2050
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CLINICAL RELEVANCE
The isoforms of apolipoprotein E (ApoE)
ApoE is a serum protein and is involved in the transport, storage
and metabolism of cholesterol. The ApoE-gene has three more frequently
occurring alleles, e2, e3 and e4, which encode the protein isoforms
ApoE2, E3 and E4. The three isoforms differ at two sites ("site"
A and "site" B) in their amino acid sequences. At the sites
A/B, E2, E3 and E4 contain the amino acids cysteine/cysteine, cysteine/arginine
and arginine/arginine respectively (1). e3 is the most common allele.
About 95% of the Caucasian population carries at least one e3 allele,
27% an e4 allele and 16% an e2 allele (2).
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The risk allele ApoE-
e4 in Alzheimer's disease
Alzheimer's disease is the most frequent cause of senile dementia
(3). According to the point of its breaking out, the disease can be
divided into an early and a late form. Both forms have strong genetic
components. Up until the present time, three genes have been described
which are involved, in a mutated form, in the development of early
Alzheimer's disease (4). Until now, only one gene has been described
as increasing, to a certain extent, the probability of developing
the disease in its late form: the gene for apolipoprotein E.
In 1993, a connection between the allele ApoE-e4 and the late form
of Alzheimer's disease was first published (5), and has been confirmed
since then in numerous studies (6-8). In fact, 65% of all pathologically
confirmed Alzheimer patients carry at least one e4 allele (7) and
12 -15 % are homozygous for e4, compared with approximately 1 - 3
% homozygous carriers among healthy test persons. (4).
Exactly how ApoE4 influences the pathogenesis of Alzheimer's disease
is being intensively researched at the moment. It is thought that
the ApoE- e4 gene product could be involved in the production and
deposal of senile plaques made of b-amyloid and degenerated nerve
cells (4).
In contrast to the genes in the early form of the disease, the presence
of an ApoE- e4 allele does not determine the disease, but rather serves
as a risk factor, especially in e4-homozygous individuals. The e4
alleles increase the risk of Alzheimer's disease at a certain age.
The ApoE genotype gives, above all, information on the age at which
the patient is predisposed towards the disease (6). According to Seshadri
et al. 95 (9), the risk of contracting Alzheimer's disease at the
age of 65 years or older is on average 15%, in carriers of an e4 allele
the risk increases to 30%, and is, in individuals without an e4 allele,
only 9%. A gene dosis effect can be observed. Each e4 allele decreases
the age at which the disease will probably first break out by 4-5
years. (10).
In itself, the ApoE- e4 is neither sufficient nor necessary for the
development of Alzheimer's disease. For this reason, various committees
have advised against carrying out a typing merely to predict the probability
of the disease (11). However, an ApoE genotyping can increase the
specificity of the clinical diagnosis of Alzheimer's disease (7) and
thereby help reduce the rate of false positive diagnoses. Genotyping
should therefore only be carried out on patients with the clinical
criteria for Alzheimer's disease.
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The risk allele ApoE-
e2 in hyperlipoproteinaemia type III
Hyperlipoproteinaemia type III is a genetic disease in which raised
levels of triglyceride and cholesterol in plasma are caused by insufficient
purification of the blood from residual lipoprotein particles (remnants).
This results in heart and circulation disease at an early age (12).
ApoE is a constituent of various lipoproteins. The protein is involved
in the decomposition of remnants in the liver, by specific interaction
with the so-called LDL receptor.The protein isoform ApoE2 has a lowered
affinity for the LDL receptor (1).
In most cases, hyperlipoproteinaemia is associated with the risk allele
ApoE-e2. According to a recent study, 94.4% of the patients are homozygous
for e2 (13).
Inversely, only approximately 2% of patients homozygous for ApoE-e2
develop the clinical phenotype of hyperlipoproteinaemia type III (14).
It is therefore thought that further genetic or environmental factors
must be involved in the development of the disease.
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Literature
(1)
Mahley RW, Huang Y (1999)
Apolipoprotein E: from atherosclerosis to Alzheimer´s disease
and beyond
Curr Opin Lipidol 10: 207-217
(2)
Houlston RS, Snowden C, Green F ... (1989)
Apolipoprotein (apo) E genotypes by polymerase chain reaction and
allele-specific oligonucleotide probes
Hum Genet 83: 364-368
(3)
Price DL, Sisodia SS, Borchelt DR (1998)
Alzheimer disease - when and why?
Nature Genetics 19: 314-316
(4)
Blacker D, Tanzi RE (1998)
The Genetics of Alzheimer Disease
Arch Neurol 55: 294-296
(5)
Strittmatter WJ, Saunders AM, Schnechel D ... (1993)
Apolipoprotein E: high avidity binding to b-amyloid and increased
frequency of type 4 allele in late-onset familial Alzheimer disease
Proc Natl Acad Sci USA 90: 1977-1981
(6)
Meyer MR, Tschanz JT, Norton MC ... (1998)
APOE genotype pedicts when - not whether - one is predisposed to develop
Alzheimer disease
Nature Genetics 19: 321-322
(7)
Mayeux R, Saunders A, Shea S ... (1998)
Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer`s
Disease
New Eng J of Med 19: 506-511
(8)
Lopez O, Lopez-Pousa S, Kamboh MI ... (1998)
Apolipoprotein E Polymorphism in Alzheimer´s Disease: A Comparative
Study of Two Research Populations from Spain and the United States
Eur Neurol 39: 229-233
(9)
Seshadri S, Drachman DA, Lippa CF (1995)
Apolipoprotein E e4 allele and the lifetime risk of Alzheimer´s
disease
Arch Neurol 52: 1074-1079
(10)
Lovestone S (1999)
Early diagnosis and the clinical genetics of Alzheimer`s disease
J Neurol 246: 69-72
(11)
McConnell LM, Koenig BA, Greely HT ... (1998)
Genetic testing and Alzheimer disease: Has the time come?
Nature Medicine 7: 757-759
(12)
Mahley RW, Huang Y, Rall SC Jr (1999)
Pathogenesis of type III hyperlipoproteinemia
J Lipid Res 40: 1933-1949
(13)
Feussner G, Feussner V, Hoffmann MM ... (1998)
Molecular basis of type III hyperlipoproteinemia in Germany
Hum Mutat 11: 417-423
(14)
Civeira F, Pocovi M, Cenarro A ... (1996)
ApoE variants in patients with type III hyperlipoproteinemia
Atherosclerosis 127: 273-282
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