The genetic correlates of survival to advanced age without Alzheimer Disease (AD) are a tractable target for discovery. A large collection of subjects is available who enter Alzheimer Disease Center (ADC) programs non-demented and are then followed through either conversion to AD or maintenance of non-AD clinical status. Longitudinal clinical and neuropsychological data, DMA and/or brain tissue and neuropathological data exist for many of these individuals. This resource, along with high-throughput SNP (single nucleotide polymorphism) genotyping technology, provides a unique opportunity for identifying genetic variations associated with AD-free survival. We have identified approximately 300 autopsy-confirmed AD subjects collected prospectively at eight collaborating ADC sites, and over 400 deceased subjects of advanced age with no clinical manifestation of dementia just prior to death (""""""""non-demented""""""""). We will generate > .100,000 genome-wide SNP genotypes for each of these subjects, using the Affymetrix GeneChip(r) Mapping 100K SNP Assay. We will then conduct a genome-wide, case-control SNP association study, using """"""""set association"""""""" methods, to identify genetic variants related to delay in age at onset of dementia. In addition, based on autopsy data, we will assign the non-demented subjects to one of three categories of pathological status (low, intermediate or high) representing the likelihood of neuropathological processes leading to AD (NIA/Reagan criteria). Using the genome-wide SNP genotype data generated for these subjects, we will conduct a case-control SNP association study, as in specific aim 1, to identify genetic variants related to maintenance of cognitive function in the presence of neuropathological damage. In collaboration with the National Alzheimer's Coordinating Center (NACC), we will develop a SNP database registry for the 700+ subjects in this study, designed with a web-based, graphical user interface with customized options for data queries and reports. These data will be available primarily through the NACC website for dissemination to the AD and aging research community. Access will also be available through the OHSU ADC Genetics Core.
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