Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease

Lehtimäki, Terho; Pirttilä, Tuula; Mehta, Pankaj; Wı́sniewski, Henryk M.; Frey, H.; Nikkari, T.

doi:10.1007/bf00225071

Cited by 118 publications

(61 citation statements)

References 26 publications

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“…3 Low levels ofapo E occur in CSF ofMS patients but could result from decreased production of apo E, increased clearance of apo E from the neurofil, or local accumulation, as reported in the senile plaques of AD. 6 The lack of association ofa particular apo E genotype with MS may not suggest a genetically determined diminution of apo E secretion.…”

Section: Resultsmentioning

confidence: 99%

Apolipoprotein E Polymorphism in Multiple Sclerosis

et al. 1998

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Additional key phrases: apo E genotype; central nervous systemApolipoprotein E (apo E) is a polymorphic plasma protein involved in cholesterol transport. Apo E is produced and secreted in the central nervous system by astrocytes. Following peripheral nerve injury in rats, the synthesis of apo E increases 250-to 350-fold. A similar increase is observed in the central nervous system when the optic nerve and spinal cord are injured. It was suggested that apo E redistributes lipid, participates in cholesterol homeostasis in the brain and is implicated in the growth and repair of the nervous system. I Three common variants of apo E are present in the general human population, c2, d and fA coding for three isoforms (apo E2, apo E3, apo E4). These isoforms differ from each other by a single aminoacid substitution. The most frequent phenotype in the normal population is apo E3/ apo E3 and the two minor isoforms are associated with altered recognition of specific receptors. Recent genetic evidence suggests that inheritance of the c4 allele is associated with increased risk for sporadic and earlier onset of Alzheimer's disease (AD).2 In contrast, Rubinsztein found no influence of the apo E phenotype in a small group of patients with multiple sclerosis (MS).' MS is the major demyelinating disease. The increased higher incidence in women, the racial and familial clustering of MS cases and the high concordance rate in monozygotic twins (26%) compared with dizygotic twins (2'3%) and non twin siblings (1'9%), suggest that a genetic component influences susceptibility to MS. 4 We recently demonstrated that apo E concentrations in cerebrospinal fluid (CSF) and apo E intrathecal synthesis are decreased in MS patients. The reduction of CSF apo E levels may impair myelin repair and influence disease progression in MS patients.

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Section: Resultsmentioning

confidence: 99%

Apolipoprotein E Polymorphism in Multiple Sclerosis

et al. 1998

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“…It can be anticipated that the levels of free cerebral ApoE are reflected by its concentration in CSF. It has been reported, however, that the CSF concentration of ApoE is similar in both control and AD groups with different ApoE genotypes (Lehtimaki et al, 1995;Yamauchi et al, 1999), although a trend toward elevated ApoE levels in patients carrying the ⑀2 allele was observed (Lehtimaki et al, 1995). However, because the applied assays have all been designed to detect unbound ApoE, it remains possible that the levels of CSF A␤-ApoE complexes will be different among individuals with different ApoE genotypes.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity

Wilhelmus¹,

Otte-Höller²,

Davis³

et al. 2005

J. Neurosci.

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The ⑀4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the ⑀2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-␤ 1-40 peptide (A␤ 1-40 ) with the 22 Glu3 Gln "Dutch" mutation caused pericyte death in vitro by a mechanism that involves A␤ fibril-like assembly at the cell surface. It is known that ApoE binds to A␤ and may modify its biological activities. In the present study, we evaluated the effect of ApoE on A␤-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an ⑀4/⑀4 genotype were more vulnerable to A␤ than cultures with an ⑀3/⑀3 or ⑀3/⑀4 genotype. The one cell culture with the ⑀2/⑀3 genotype was relatively resistant to A␤ compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against A␤-mediated toxicity of cerebrovascular cells and, in addition, ApoE ⑀2/⑀3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with ⑀4/⑀4 cells. Thus, the disparity between ApoE genotype and A␤-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of A␤ cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to A␤ and thereby modify A␤-mediated cell death.

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“…However, other studies have failed to replicate Molecular Psychiatry this finding. [48][49][50][51] Whilst consensus on this issue is yet to be reached, it is interesting to note that studies have shown that apoE deficiency virtually abolishes cerebral amyloidosis in amyloid plaque-forming transgenic mice. 52,53 In the current study, plasma apoE levels were not found to be significantly elevated among 'memory complainers'.…”

Section: Discussionmentioning

confidence: 99%

APOE-ε4 and APOE −491A polymorphisms in individuals with subjective memory loss

et al. 2002

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The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the ⑀4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, −491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, −491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the ⑀4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the −491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P Ͻ 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the ⑀4 allele of apolipoprotein E and the −491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.

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Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease

Cited by 118 publications

References 26 publications

Apolipoprotein E Polymorphism in Multiple Sclerosis

Apolipoprotein E Polymorphism in Multiple Sclerosis

Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity

APOE-ε4 and APOE −491A polymorphisms in individuals with subjective memory loss

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