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Whole Exome Analysis of Early Onset Alzheimer's Disease

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Technical Report,01 Mar 2012,30 Jul 2018

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University of Miami Miami United States

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The primary focus toward identification of Alzheimer disease AD risk genes over the past five years has been testing the common disease common variant CDCV hypothesis through the use of genome-wide association studies GWAS in late onset Alzheimer disease LOAD. While common variation clearly plays a role in AD there is a growing realization that the CDCV hypothesis is unlikely to explain all the genetic effect underlying AD. One alternative hypothesis invokes multiple rare variants RV in one or more genes, each with stronger individual effects than CDCV genes. We designed this project to test the rare variant hypothesis in AD by examining those cases with the most severe phenotype as determine by early onset EOAD, cases with AAO 60 years. Although there are three known EOAD genes PS1, PS2 and APP they account for only 60-70 of familial EOAD and even less of sporadic EOAD. Thus, the majority of the genetics of EOAD remains unknown. Until now, large extended families with AD in multiple generations were necessary to identify variants of significant effect contributing to AD risk, however, with the advent of new genomic technologies such as high-throughput sequencing technology, small family aggregates and isolated cases, particularly those with an extreme phenotype of the disorder such as early onset can be used. Thus, we will utilize whole exome high-throughput sequencing to identify high risk AD variants that we will further characterize with respect to AD. We will examine both Caucasian and Caribbean Hispanic AD populations. Our two pronged approach includes structural characterization at the DNA level Dr. Pericak-Vance, and analysis of Caribbean Hispanics Dr. Richard Mayeux. Comparing across populations will be extremely useful. Specifically, high priority RVs identified through the whole exome analysis will be further explored with multiple strategies.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology

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