Presentation Abstract

Session: Hot Topics 1
Sunday, Jul 12, 2009, 3:00 PM - 5:00 PM
Presentation: O1-06-01 - Apoe-3 And Tomm-40 Haplotypes Determine Inheritance Of Alzheimer's Disease Independently Of Apoe-4 Risk
Pres. Time: Sunday, Jul 12, 2009, 3:00 PM - 3:15 PM
Location: Lehar
Author(s): Allen D. Roses1,2, Michael W. Lutz1,2, Matthew J. Huentelman3,4, Ornit Chiba-Falek1,5, Kathleen A. Welsh-Bohmer1,6, Eric M. Reiman7,4, 1Duke University, Durham, NC, USA; 2Deane Drug Discovery Institute, Durham, NC, USA; 3Translational Genomics Research Institute, Phoenix, AZ, USA; 4University of Arizona, Phoenix, AZ, USA; 5Institute for Genomic Sciences and Policy, Durham, NC, USA; 6Alzheimer's Disease Clinical Center, Durham, NC, USA; 7Banner Alzheimer's Institute, Phoenix, AZ, USA. Contact e-mail: allen.roses@duke.edu
Abstract: Background:
The association of apolipoprotein E (APOE) genotypes, particularly APOE ε4 (APOE4), with the risk and age of onset of Alzheimer’s disease remains the most confirmed genetic association for any complex disease. Estimates of the heritability of APOE4 for late onset AD range from 58% to 79%, and the population attributable risk due to the APOE4 allele is between 20% and 70%.
Objective:
These estimates suggest that other genetic variants and/or interactions between variants incur additional disease risk and modify age of onset distributions. Genome wide scan association results for AD have consistently reproduced the extraordinary association of the LD region containing APOE. TOMM40, the protein translocase of the outer mitochondrial membrane, is in high LD with APOE, and codes for the membrane channel through which cytoplasmic peptides and proteins traverse in order to synthesize new mitochondria. Our objectives were to identify additional haplotypes within the LD region that increase the estimates of heritability.
Methods:
We examined the LD region containing both APOE and TOMM40 using deep (10X) primary sequencing in AD patients and controls. We performed phylogenetic analyses of the LD region covering TOMM40 and APOE in 66 patients and 66 age-matched controls with respect to risk and age of onset distribution.
Conclusion:
We found that unique and distinct inherited families of different TOMM40 variants are located on the same genomic interval as APOE3, but not on the APOE4-containing genomic interval and can either increase or decrease the age of risk distribution of AD. Therefore the genetic inheritance of these TOMM40 variants are independent of the inheritance of APOE4, effectively providing a differentiation of two distinct forms of APOE3 - those linked to TOMM40 haplotypes that increase riskand decrease age of onset, and those that decrease risk. These data increase the accuracy of genetic age of onset risk, dependent on age, APOE and TOMM40 genotypes and provide the opportunity to define high risk of AD over the next 5-7 years, versus lower risk of AD. The prospective predictive validation of this predictive diagnostic is planned to be performed simultaneously with an AD prevention clinical trial [Zinfandel Pharma].
Disclosures:   A.D. Roses, Deane Family Trust; Zinfandel Pharmaceuticals, Inc.
EMBARGO: All materials to be presented at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) are embargoed for publication and broadcast until the date and time of presentation at ICAD 2009, unless the Alzheimer's Association provides written notice of change of date/time in advance.



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