Variation at the apolipoprotein E locus and risk for Alzheimer's disease: Cladistic analysis

The ε4 variant of the apolipoprotein E (apoE) gene is a potent susceptibility factor for Alzheimer's disease (AD). There are three common alleles, ε2, ε3, and ε4 resulting in six genotypic combinations. A gene dose effect is apparent in AD where bearers of one ε4 allele are at intermediate risk between ε4 homozygotes and non-ε4 bearers (odds ratios range between 4.9-34.3 and 1.65-5.1, respectively). Although the evidence for ε4 as a susceptibility gene is compelling, many familial and sporadic AD cases have no ε4 allele (29 and 38%, respectively), suggesting other risk factors predispose to AD. Variations in the promoter region of the apoE gene have recently been reported to incur differential risk for AD, which cannot be explained by linkage disequilibrium with the ε4 allele since the effect was present in non-ε4 bearers. To further investigate the risk for AD associated with the apoE region, Templeton [1995] used cladistic analysis to reconstruct the evolutionary relationships among extended haplotypes spanning approximately 20 kb in the region including apoE and apoCI. Haplotypes bearing the ε4 allele were found to be associated with heightened risk, but so were a subset of haplotypes bearing the carrying ε3 allele. The evolutionary transition to the ε4 allele was not found to be associated with increased risk. These findings support the existence of additional risk factors that act independently of apoE. We have used cladistic analysis to readdress the findings of Templeton in a larger independent case-control sample and to further investigate the contribution of the apoE promoter variants to the risk for AD.