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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Roses, AD; Lutz, MW; Amrine-Madsen, H; Saunders, AM; Crenshaw, DG; Sundseth, SS; Huentelman, MJ; Welsh-Bohmer, KA; Reiman, EM

Published Date

  • October 2010

Published In

Volume / Issue

  • 10 / 5

Start / End Page

  • 375 - 384

PubMed ID

  • 20029386

Pubmed Central ID

  • PMC2946560

Electronic International Standard Serial Number (EISSN)

  • 1473-1150

Digital Object Identifier (DOI)

  • 10.1038/tpj.2009.69


  • eng

Conference Location

  • United States