Alzheimer's disease (AD) is the most common neurodegenerative disease with no effective means of prevention or treatment. Most of the recent published genetic studies for AD have focused on the identification of genetic variants associated with risk for disease. Other aspects of AD, such as age at onset, disease duration or rate of disease progression are less well studied. It is very likely that different genetic variants and genes will influence these different aspects of disease. The goal of this study is to identify novel genetic variants and genes associated with rate of disease progression and other informative endophenotypes for AD, such as amyloid imaging (Pittsburgh compound B or florbetapir) and hippocampal volume. We will use innovative genomic and statistical methods, to analyze not only the effect of common variants but also rare coding variants on endophenotype levels by incorporating genome-wide association data, whole-genome sequencing and exome-chip data into our analyses. We will also test whether the variants associated with rate of progression, amyloid imaging and hippocampal volume are also associated with risk for disease, cerebrospinal fluid tau and A? levels and other AD phenotypes. The broad, long-term goal of this research is to dissect the complex genetic architecture of Alzheimer's disease, which will lead to better prediction and treatment of this devastating disease. By studying several AD endophenotypes we expect to identify genetic variants, genes and pathways affecting different aspects of the disease. These findings will help to identify novel and key proteins involved in disease pathogenesis and potential therapeutic targets.

Public Health Relevance

As instructed by the funding opportunity announcement for this application (PAR-13-329), only the Overall component contains a project narrative. Cores and projects were instructed not to include this section.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
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Washington University
Saint Louis
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