Disease relevance of APOE  

• CONCLUSIONS: These preliminary findings suggest that possession of an APOE epsilon4 allele may be associated with increased severity of chronic neurologic deficits in high-exposure boxers [1].
• INTERPRETATION: Our findings show a significant genetic association of APOE polymorphism with outcome after head injury supporting the hypothesis of a genetically determined influence [2].
• 17 (57%) of 30 patients with APOE epsilon4 had an unfavourable outcome (dead, vegetative state, or severe disability) compared with 16 (27%) of the 59 patients without APOE epsilon4 (p=0.006) [2].
• Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis [3].
• In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE [4].

Psychiatry related information on APOE

• This effect of the APOE epsilon 4 allele on normal cognitive ageing may be mediated by a mechanism that is at least partly independent of its predisposing effect towards Alzheimer's disease [5].
• Risks associated with APOE epsilon4 were elevated regardless of the subtype of dementia with stroke or age or sex [6].
• OBJECTIVE: To investigate the association between the apolipoprotein E (APOE) genotypes and dementia in patients with stroke, defined as either vascular dementia (VaD) or Alzheimer disease with cerebrovascular disease (AD with CVD) [6].
• OBJECTIVE: To determine if the APOE epsilon4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults [7].
• APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss [8].
• This suggests that among individuals with a family history of AD and the APOE epsilon4 allele, additional genetic or environmental factors may accelerate the onset of dementia [9].

High impact information on APOE

• Here, we present the crystal structures of the ligand binding region of SdrG as an apoprotein and in complex with a synthetic peptide analogous to its binding site in Fg [10].
• One candidate is the apolipoprotein E gene, since both the epsilon2 and the epsilon4 alleles of apolipoprotein E appear to be associated with the severity of amyloid angiopathy [11].
• To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition [12].
• BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life [12].
• Carriers of the epsilon2 or epsilon4 allele had a two-year rate of recurrence of 28 percent, as compared with only 10 percent for patients with the common apolipoprotein E epsilon3/epsilon3 genotype (risk ratio, 3.8; 95 percent confidence interval, 1.2 to 11.6; P=0.01) [11].

Chemical compound and disease context of APOE

• To examine whether APOE might be synthesized by human neurons, we performed in situ hybridization on paraffin-embedded and frozen brain sections from three nondemented controls and five Alzheimer's disease (AD) patients using digoxigenin-labeled antisense and sense cRNA probes to human APOE [13].
• OBJECTIVES: The apolipoprotein epsilon 4 allele (APOE/epsilon 4) increases plasma cholesterol level and the risk for the late onset type of Alzheimer's disease [14].
• RESULTS: In human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population [15].
• OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease [16].
• However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia [15].

Biological context of APOE

• We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control [17].
• An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APP) gene (APP717 and APP670/671)13 carrying the APOE epsilon-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations, or in chromosome 14-linked familial AD patients [18].
• RESULTS: Overall, patients with dementia and stroke had a higher APOE epsilon4 allele frequency than controls [6].
• Compared with APOE epsilon3 homozygote individuals, APOE epsilon4 homozygotes had a 7-fold increased risk of dementia with stroke (OR=6.9; 95% CI, 1.6-29.4), while APOE epsilon4 heterozygotes had nearly a 2-fold increase in risk (OR=1.8; 95% CI, 1.2-2.7) [6].
• Genetic linkage and association studies have also shown that the epsilon4 allele of the apolipoprotein E (APOE) gene increases risk for AD in a dose-dependent manner in both familial and sporadic forms of AD and may account for as much as 50% of the attributable risk [19].

Anatomical context of APOE

• More people who die from head injuries than non-head-injured controls have deposits of amyloid beta-protein in the cerebral cortex, with amyloid beta-protein deposits present predominantly in patients with the APOE epsilon4 allele [2].
• When a model of multiple linear regression was used to compare the relative influence of APOE genotype, sex, disease duration, age at death, diffuse and neuritic plaques as well as neurofibrillary tangles on microglial activation, only APOE genotype was found to have a significant effect [20].
• The number of activated microglia and the tissue area occupied by these cells increased significantly with APOE epsilon4 gene dose [20].
• In cerebellar cortex, APOE mRNA was seen only in Bergmann glial cells and scattered astrocytes but not in Purkinje cells or granule cell neurons [13].
• The important new finding is that APOE mRNA is also transcribed and expressed in many neurons in frontal cortex and human hippocampus but not in neurons of cerebellar cortex from the same brains [13].

Associations of APOE with chemical compounds

• The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD [21].
• CONCLUSIONS: In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge [7].
• APOE/epsilon 4 also significantly contributed to a 2.9% increase of total cholesterol, 11.8% increase of triglyceride and 3.2% of decrease of high-density lipoprotein-cholesterol [14].
• The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites [22].
• Also, very modest genotype-phenotype associations were observed between APOE genotype (P = 0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial, glucose concentration (P = 0.048) [23].

Physical interactions of APOE

• Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor [24].
• Also, LPL-induced binding to cells was blocked by an anti-LPL monoclonal antibody but not by antibodies that are known to block apolipoprotein E- or B-100-mediated binding to low density lipoprotein (LDL) receptors [25].
• ApoE is able to interact with the LDL receptor only when it is bound to lipid particles [26].
• APP cleavage products are also able to prevent cholesterol binding to APOE [27].
• Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease [28].
• APOE binds to glycoprotein C of the Herpes simplex virus (HSV-1) ref

Co-localisations of APOE

• In affected regions of AD brain, ACT and APOE colocalize with Abeta deposits and reactive microglia and astrocytes [29].
• While apolipoprotein E (ApoE) and beta-amyloid (A beta) co-localize in senile plaques in cortex and cerebellum in Alzheimer disease (AD), the A beta-positive, predominantly diffuse plaques in the striatum do not exhibit ApoE immunoreactivity regardless of disease duration [30].
• Type I familial amyloid polyneuropathy (FAP) is one form of systemic amyloidosis in which ApoE co-localizes with amyloid deposits [31].

Regulatory relationships of APOE

• Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux [32].
• Herein, we examine whether APOE genotype influenced the species of Abeta peptide deposited [33].
• HTGL-stimulated binding and internalization of apoprotein-free emulsions was totally abolished by heparinase indicating that it was mediated by HSPG [34].
• Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status [35].
• Apolipoprotein E genotype regulates amyloid-beta cytotoxicity [36].

Other interactions of APOE

• ApoE is found in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease [37].
• Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene [38].
• Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk [39].
• The virus associates with serum lipoproteins, including those containing apolipoprotein E (apoE) and apolipoprotein B (apoB), and may enter cells via the low-density lipoprotein receptor (LDLR) [40].
• Both apolipoprotein E and its receptor, the low-density-lipoprotein receptor-related protein (LRP), are associated with senile plaques in Alzheimer's disease [41].

Analytical, diagnostic and therapeutic context of APOE

• The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group [42].
• METHODS: In a cross-sectional study, the authors investigated 374 patients with clinically definite MS and a disease duration of at least 3 years and related their clinical and demographic findings to the allelic polymorphism of the APOE gene [43].
• OBJECTIVE: The aim of this study is to clarify the conflicting results of the epsilon2/epsilon3/epsilon4 APOE polymorphism as a risk factor on diabetic nephropathy by a cohort study [44].
• Genetic polymorphisms within the APOC3, APOE, APOAIV, and LPL genes were determined by a multiplex PCR [45].
• STUDY SELECTION: Case-control studies using clinical or pathologic criteria for PD and dementia, and with complete APOE genotype frequencies data [46].

References