Genetic variation at a single locus and age of onset for Alzheimer's disease

This perspective article provides an opportunity to explain a new genetic finding for late-onset Alzheimer's disease (LOAD). It is specifically written for physicians and scientists who are interested in LOAD, but it may be relevant to those interested in identifying susceptibility variants for other complex diseases. The significant finding discussed here is that a variable-length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene is associated with the age of onset of LOAD [Roses AD, Lutz MW, Amrine-Madsen H. Saunders AM, Crenshaw DG, Sundseth SS, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J 2009 December 22;[Epublication ahead of print]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium (LD) block that contains the TOMM40. APOE, and APOC I genes from patients with LOAD and age-matched subjects without disease. Although the data will have diagnostic, prognostic, and therapeutic strategy implications, this perspective is meant to place the inheritance pattern for this "complex" human disease into context, and to highlight the potential utility of applying phylogenetic tools to the study of the genetics of complex diseases. (C) 2010 The Alzheimer's Association. All rights reserved.