The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes

• Published in: Alzheimer's & dementia Vol. 14; no. 5; pp. 692 - 698
• Main Authors: Chiba-Falek, Ornit, Gottschalk, William K., Lutz, Michael W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2018
• Subjects: APOE; Brain imaging; Cognitive performance; Late-onset Alzheimer's disease; TOMM40 poly-T; TOMM40 poly-T; Late-onset Alzheimer's disease; Cognitive performance; Brain imaging; APOE
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1016/j.jalz.2018.01.015

The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzheimer's disease (LOAD). Following the original discovery, additional studies found associations between the TOMM40 poly-T and LOAD-related phenotypes independent of APOE genotypes, while others did not replicate these associations. Furthermore, the identity of the TOMM40 poly-T risk allele has been controversial between different LOAD-related phenotypes. Here, we propose a framework to address the conflicting findings with respect to the TOMM40 poly-T allele associations with LOAD phenotypes and their functional effects. The framework is used to interpret previous studies as means to gain insights regarding the nature of the risk allele, very long versus short. We suggest that the identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated, the ages of the study subjects at the time of assessment, and the context of the APOE genotypes. In concluding remarks, we outline future studies that will inform the mechanistic interpretation of the genetic data. •TOMM40 poly-T has autonomous associations with late-onset Alzheimer's disease–related phenotypes.•The direction of the TOMM40 poly-T effects are influenced by interactions with APOE.•The identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated and the ages of the study subjects.