38,40,135,140,141 The APOE gene in humans contains three main polymorphisms, ε2, ε3, and ε4, of which ε3 is the most common (75%). The ε3 polymorphism contains a cysteine at codon 112 and an arginine at codon 158. The ε4 polymorphism represents an arginine at codon 112 and was found to strongly associate with

late-onset AD.133-139 Persons homozygous for ε4 have almost a 15-fold higher risk of developing AD, and persons heterozygous for ε4 have a 3fold higher risk than those who do not carry this allele.142,143 Inhibitors,research,lifescience,medical This dose-response relationship provides a strong argument for the APOE polymorphism being a contributing factor for AD. The ε2 polymorphism contains a cysteine at codons 112 and 158, and has also been found to associate with late-onset AD.134 In addition, it has Inhibitors,research,lifescience,medical been reported that the e4 polymorphism or a polymorphism in the promoter selleck chemicals Veliparib region is associated with early-onset AD.135,144 Furthermore, polymorphisms within the

promoter regions of the APOE gene, such as the region at 491 amino acids upstream of the APOE transcriptional start site (-491 A/T), were also found to associate with AD.145,148 It has been shown that these polymorphisms (ie, at -491 A/T and at the e4 allele) are independent genetic risk factors.37 A study of 5.5 kb of the APOE gene found at least 22 single nucleotide polymorphisms (SNPs). These SNPs generate Inhibitors,research,lifescience,medical 31 distinct haplotypes and 7 SNPs were found

in promoter region.149 A role for these polymorphisms in pathogenesis of AD has not been Inhibitors,research,lifescience,medical shown.40 Despite these robust association results, there are still conflicting reports. A major discrepant finding came from studies in African-American and new Hispanic populations, which did not find any association of the ε4 allele with AD.150-152 Also, Inhibitors,research,lifescience,medical it is not clear why some homozygotes of ε4 still do not show any obvious AD symptoms, even when they are in their nineties. On the other hand, most AD patients do not harbor an ε4 allele.17 In addition, some studies indicate no increased risk factor for AD with the promoter (-491 A/T) genotype in Caucasian,153 Japanese,67,154 or Chinese155 populations. It is reasonable to consider that the APOE polymorphism is only a genetic risk factor, but not a causative gene. Cilengitide This is also evidenced by the finding that many other factors, such as head injury,156,157 spontaneous intracerebral hemorrhage,158 and heart surgery159 facilitate the association of APOE polymorphism with AD. The mechanism by which the APOE gene is implicated in AD pathogenesis is still unclear. The current hypothesis is that APOE ε4/ε2 polymorphisms may affect the production, distribution, or clearance of Aβ. There is evidence to show that APOE genotype is a factor affecting the age of onset of AD with the London APP mutation, suggesting a direct biochemical interaction between APOE and Aβ.