APOE and TOMM40 in Alzheimer’s Disease: A Case of Mistaken Identity,Using Precision Tools but with Loss of Accuracy

Abstract

Copyright: © 2015 Roses AD. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. “The association of the apolipoprotein E (APOE) e4 allele with AD is strong (odds ratios ranging from 3 to 10) and undisputed” [1]. In fact, in 2015 this remains generally true, yet this same paper falls to mention the association with the poly-T variant (rs10524523) in the TOMM40 gene (aka TOMM40’523) which encodes the channel component of the complex that transports proteins across the outer mitochondrial membrane. The same research group published in Archives of Neurology in 2012 a widely quoted editorial entitled “TOMM40 Association with Alzheimer’s disease: Tales of APOE and Linkage Disequilibrium” [2]. In this article, Guerreiro and Hardy made the case that although APOE and TOMM40 were adjacent to each other on chromosome 19, and in linkage disequilibrium [LD]; the association of TOMM40 was entirely due to its position in LD with APOE. To further support this argument, the authors stressed that, “since the first genome-wide association studies in AD it was clear that no other locus in the genome would present such a strong association with the disease as that on chromosome 19 around the APOE locus” [2]. What the authors failed to comprehend or consider was that the GWAS SNPs representing the APOE region were actually four TOMM40 SNPs and a 3 non-coding SNP near APOE, not either coding SNPs of APOE. The two coding SNPs that determine the differences between APOE4, APOE3, and APOE2 alleles are not present in the genotyping platforms typically used in GWAS studies. Simply stated, it was TOMM40 SNPs being measured, not APOE SNPs and therefore a case of mistaken identity. Identity is equivalent to accuracy.