![]() Characterized APOE promoter polymorphisms include −491, −427, −219 (Th1/E47cs), and +113. Because plasma apoE is produced by the liver and CSF apoE is secreted by brain glial cells, it appears that apoE and possibly apoE isoforms may be metabolized or regulated differently in the two compartments.ĪPOE regulatory elements and apoE expressionĪD risk has been reported to be associated with APOE promoter polymorphisms directly upstream of the transcription start site. In contrast, the opposite proportion is present in CSF, suggesting a differential metabolism or regulation of apoE isoforms depending on the biological compartment measured plasma or CSF. report that apoE plasma levels are lower in AD compared to the mildly cognitively impaired and APOE e3/e4 heterozygotes have a higher proportion of the apoE E3 isoform than the E4 in plasma. In addition, APOE ε4 appears not to be associated with CSF apoE levels in healthy populations or AD, but is associated with lower apoE plasma levels in healthy subjects. CSF apoE levels in healthy populations appear to be associated with age, but not with gender although one study did not find an association with age. Studies thus far indicate CSF apoE is either lower in AD or has no association with AD. There is no clear consensus on whether cerebrospinal fluid (CSF) apoE levels are associated with AD. However, a family history of dementia is associated with an increased risk of AD in the elderly only among APOE ε4 carriers and a large proportion of APOE ε4 carriers who survive into old age remain cognitively normal suggesting other genetic factors besides APOE ε4 play a role in AD. ![]() The APOE ε4 allele, defined by the rs429358 SNP, and age are currently the only risk factors strongly associated with late onset Alzheimer’s disease (AD). In addition, apoE isoforms appear to influence plasma cholesterol levels, neuronal growth and amyloid deposition. Structural consequences of the exon 4 APOE haplotype appear to be that the apoE E4 protein binds preferentially to plasma very low density lipids (VLDLs) whereas apoE E2 and E3 bind preferentially to plasma high density lipoproteins (HDLs). The apoE protein exists in three extensively studied isoforms, E2, E3, and E4 that are the result of two non-synonymous SNPs, rs429358 and rs7412, located in exon 4 of the APOE gene. It is the major apolipoprotein synthesized in the brain. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.Īpolipoprotein E (apoE) is involved in lipid transport and binds to cell surface receptors to mediate lipoprotein uptake. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. APOE ε4 genotype does not predict CSF apoE levels. ![]() Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age ( n = 134). The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. ![]() Multiple loci in and outside of APOE are associated with a high risk of AD. ![]() Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. The ε4 allele of the apolipoprotein E gene ( APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer’s disease (AD). ![]()
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