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Genetic variation at a single locus and age of onset for Alzheimer's disease
Michael W. Lutz, Donna G. Crenshaw, Ann M. Saunders, Allen D. Roses Alzheimer's & Dementia: The Journal of the Alzheimer's Association Volume 6, Issue 2, Pages (March 2010) DOI: /j.jalz Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 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 rs Note that APOE ɛ3-long “523” and APOE ɛ4 haplotypes separate into clade A. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 2 Poly-T repeats linked to APOE ɛ3 and APOE ɛ4. These histograms show the frequency distributions of lengths of the deoxythymidine homopolymers (number of T residues) at rs in linkage with APOE ɛ3 (top panel) or APOE ɛ4 (bottom panel). The three different categories of length are significantly different from each other. This is the analysis from one case/control cohort representing 210 chromosomes. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 3 Diagram of exons 6 (E6) –10 (E10) of TOMM40. The vertical lines represent SNPs that distinguish clades A and B, including rs ; purple boxes in intron 6 indicate the locations of two poly-T tracts. The histogram indicate the frequency distribution of poly-T lengths at one locus, including rs Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 4 Average age of LOAD diagnosis for APOE ɛ3/ɛ4 heterozygous individuals. “Long” refers to APOE ɛ3-very long poly-T haplotype; “Short” refers to APOE ɛ3-short poly-T haplotype. All individuals carried one copy of the APOE ɛ4-long poly-T haplotype. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 5 Age of onset curves for individuals with the indicated genotypes using the information available in (Modified from Corder EH, et al. Science 1993;261:921–3). Today we propose that each of the age of onset curves is an average of sub-curves. There are two curves for APOE ɛ3/ɛ4 individuals due to the presence of either a short or a long “523” polymorphisms linked to APOE ɛ3. There are likely three curves for APOE ɛ3/ɛ3 individuals due to the possible combination of alleles at “523,” ie, short/short, short/very long, and very long/very long. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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Fig. 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. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2010 6, DOI: ( /j.jalz ) Copyright © 2010 The Alzheimer's Association Terms and Conditions
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