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

Abstract

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 APOC1 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.

Figure 1. Phylogenetic tree that resolved with strong bootstrap support and without prior consideration of APOE allele for a 10 Kb region in the TOMM40-APOE LD block

A and B refer to the two clades at the first branch point; the boxed regions identify haplogroups of the indicated APOE allele and poly-T length polymorphism at rs10524523. Note that APOE3-long “523” and APOE4 haplotypes separate into clade A.

Figure 2. Poly-T repeats linked to APOE3 and APOE4

These histograms show the frequency distributions of lengths of the deoxythymidine homopolymers (number of T residues) at rs10524523 in linkage with APOE3 (top panel) or APOE4 (bottom panel). The three different categories of length are significantly different from each other. This is the analysis from cohort 1 cases and controls representing 210 chromosomes.

Figure 3. Diagram of exons 6 (E6) to 10 (E10) of TOMM40

The vertical lines represent SNPs that distinguish clades A and B; purple boxes in intron 6 indicate the locations of two poly-T tracts. The histograms indicate the frequency distributions of poly-T lengths at two loci.

Figure 4. Average age of LOAD diagnosis for APOE3/4 heterozygous individuals

Long refers to APOE3-very long poly-T haplotype; Short refers to APOE3-short poly-T haplotype. All individuals carried one copy of the APOE4-long poly-T haplotype.

Figure 5. Age of onset curves for individuals with the indicated genotypes using the information available in 1993

From [1]. Today we propose that each of the age of onset curves is an average of sub-curves. There are two curves for APOE3/4 individuals due to the presence of either a short or a long 523 polymorphisms linked to APOE3. There are likely three curves for APOE3/3 individuals due to the possible combination of alleles at 523, i.e. short/short, short/very long, and very long/very long.

Figure 6. Proposed clinical trial design

This study is designed to simultaneously validate the genetic marker and to test the efficacy of a therapeutic that delays the onset of LOAD.