A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease

Abstract

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5±1.2 years versus 77.6±2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921

“…26 Linkage with APOE is such that the APOE E4 allele is almost always linked to a long poly-T repeat, whereas the APOE E3 allele is linked to either a short or a very long poly-T repeat. 27 Relevant to the present study, longer TOMM40 poly-T repeats have been associated with an earlier onset of Alzheimer's disease. 27 It has been suggested that the risk of Alzheimer's disease in APOE E3 carriers with a very long TOMM40 poly-T repeat might equal, or even exceed, the risk generally associated with the APOE E4 allele.…”

“…27 Relevant to the present study, longer TOMM40 poly-T repeats have been associated with an earlier onset of Alzheimer's disease. 27 It has been suggested that the risk of Alzheimer's disease in APOE E3 carriers with a very long TOMM40 poly-T repeat might equal, or even exceed, the risk generally associated with the APOE E4 allele. 26 It is not known whether the TOMM40 poly-T variants might also have a role in nonpathological cognitive decline.…”

“…However, recent studies have suggested that the APOE E3 allele, when connected to a very long TOMM40 poly-T repeat, is associated with an earlier onset of Alzheimer's disease, comparable to the age of onset typically observed in APOE E4 carriers. 27 The present study assessed whether the APOE E3 and E4-linked TOMM40 variants might also have a role in non-pathological cognitive decline. Our results did not offer support for an interaction between APOE and TOMM40 in mediating age-related cognitive decline in the ninth decade.…”

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

“…67 For example APOC1 and TOMM40 have been associated with increased risk of AD development 68 or earlier age of AD onset. 69 Large population samples would be needed to study the contribution of other genes to WM structure and AD.…”

Apolipoprotein E region molecular signatures of Alzheimer's disease

“…However, some researchers contend that variants of other genes in the APOE region play a role in AD development. For example, the mitochondrial cascade hypothesis holds that TOMM40 plays a role in AD development through the regulation of mitochondrial biogenesis (Roses et al., 2010; Swerdlow, Burns & Khan, 2014). NECTIN2 , which flanks TOMM40 , encodes a plasma membrane component of adherens junctions that also serves as an entry mediator for certain mutant strains of herpes simplex virus.…”