An APOE Haplotype Associated with Decreased ε4 Expression Increases the Risk of Late Onset Alzheimer's Disease

Abstract

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and ε rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and ε4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/ε4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified.

The Importance of Being Connected

“…This clade is associated with a higher risk for LOAD and an earlier age of onset for LOAD relative to clade B; and 2) the T allele of −219 always co-occurs with either a long 523 allele linked to APOE 4 or a very long 523 allele linked to APOE 3. The association between the two alleles of −219 and distinct lengths of 523 potentially extends the findings of Lescai et al [10] from individuals possessing the APOE 4 allele to 3 carriers as well.…”

“…promoter SNP (rs405509 or −219T) and the two SNPs that determine the APOE 4 genotype (rs429358-rs7412 CC) that increases the risk for LOAD when the alleles are present in cis on the same chromosome [10]. Additionally, they show that this haplotype is significantly associated with younger age at diagnosis when compared to haplotypes that contain the G form of the −219 SNP and the APOE 4 allele, which suggests a link to earlier disease onset.…”

“…Additionally, they show that this haplotype is significantly associated with younger age at diagnosis when compared to haplotypes that contain the G form of the −219 SNP and the APOE 4 allele, which suggests a link to earlier disease onset. Notably, the authors stress the importance of the occurrence of the associated alleles in cis, or in phase, in their analyses [10]. Prior studies, where the phase of the alleles on the chromosome was not determined or was estimated by inference, had limited power to measure complex interactions of specific alleles at multiple polymorphic sites in the genomic interval of chromosome 19 that includes APOE and several other genes.…”

“…mosome 19 from LOAD patients and controls. This genomic region includes the three APOE promoter polymorphisms (−219, −491 and −427) discussed by Lescai et al [10]. Events such as mutation and recombination in an ancestral sequence, represented by a node in the tree, introduce diversity in each chromosome and the resultant lineages subsequently inherit the outcomes of these events.…”

“…We mapped the three APOE promoter polymorphisms (−219, −491 and −427), discussed by Lescai et al [10] to the data for the three clinical cohorts in our 2009 publication. The three SNPs in the APOE promoter tend to be in linkage with specific polyT lengths.…”