One hundred years ago, dementing illnesses were classified based upon their clinical presentation and neuropathology. The promise of the twenty-first century is that we will be able to classify these same diseases by the genetic cause or genetic risk factors, a classification based upon etiology not symptomatology. During the last two decades many genes have been shown to cause autosomal dominant forms of early onset dementing illnesses. These rare disorders have provided enormous insight into the pathogenesis of more common variants of the same diseases. In 1993, a polymorphism in the apolipoprotein E (APOE) gene was identified as the first genetic risk factor for AD. A dose-dependent effect of the APOE4 allele has now become an important variable in all studies of AD. During the last five years genome-wide association studies and next generation sequencing studies have begun to identify many novel risk factors for AD. The goal of the Genetics Core of the Knight ADRC is to provide genetic information and useful biological materials on all ADRC participants. We will obtain family history data, plasma, serum, DNA, RNA, and APOE genotypes on all ADRC participants. Blood samples on all participants will be sent to NCRAD. Many participants will also have GWAS, exome array and whole exome/genome sequence data through national and international initiatives and ADRC affiliated projects held by Drs. Goate and Cruchaga. These data will be stored in the master ADRC database and provided to investigators upon request. We will identify and assess novel multiplex kindreds. Families that meet criteria for other funded projects such as DIAN, NIA-LOAD and LEFFTDS will be invited to participate in these studies. The Core will support Projects 1, 2 and 3 of the Knight ADRC and will continue to support the Health Aging and Senile Dementia and Adult Children Study Program Project Grants (JC Morris, PI) during the next five years. New in this application we will collect skin biopsies from targeted individuals carrying specific genetic risk factors for AD and we will begin to collect blood annually for RNA expression and DNA methylation studies to enable novel biomarker programs in peripheral tissues.
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