2014 Annual Report: 10 Years of Leading Research

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Alzheimer’s Genome Project™

Funding year(s): 
2005 to 2015
Funding to date: 

The goal of this project is to evaluate our new Alzheimer’s disease gene candidates for effects on Alzheimer’s pathology and related biological pathways, including APP processing, amyloid beta protein generation, tangle formation and cell death. These studies are being carried out as part of Phase II of the Alzheimer’s Genome Project (AGP) and entail functional analyses of the Alzheimer’s gene candidates identified in Phase I of the AGP. We have focused the Phase II studies on the novel Alzheimer’s genes known as ADAM10, ATXN1 and CD33, all identified in 2008 as part of Phase I of the AGP.

The functional studies, aimed at how these genes influence risk for Alzheimer’s, are carried out in both cell-based and animal models. We also have performed genetic follow-up and functional studies for AD-associated aberrations in the human genome, known as copy number variants (CNV). This has led to the identification of several CNVs in novel Alzheimer’s genes underlying the inheritance of cases of familial early-onset Alzheimer’s that were not explained by the known early-onset Alzheimer’s genes co-discovered by our lab in the 1980s and ’90s (amyloid precursor protein, presenilin 1 and presenilin 2).

The knowledge gained from how the newly identified Alzheimer’s genes (from Phase I) biologically increase or decrease risk for Alzheimer’s disease is being implemented to design new drug discovery efforts, also as part of Phase II of the AGP. Phase III of the AGP is being carried out parallel to Phase II and includes Whole Genome Sequencing of the human genomes of subjects from both early-onset and late-onset Alzheimer’s families. The goal of Phase III of the AGP is to identify all of the biologically relevant functional gene variants that influence risk for Alzheimer’s disease. Once identified, these gene variants will be analyzed using similar methods to those described here in Phase II of the AGP. A detailed description of Phase III of the AGP can be found in the section under “Whole Genome Sequencing of Alzheimer’s Disease Families.”