Identification of Genetic Risk Factors for AD and FTD

描述（由申请人提供）：识别痴呆症的遗传基础仍然是研究的一个重要目标，其目的是提高我们对这些疾病的理解和开发新的治疗方法。在遗传性额颞叶痴呆（FTD）病例中发现的tau突变表明，tau蛋白失调可导致神经退行性疾病。但是，tau突变在AD中尚未被描述，tau突变约占家族性FTD病例的15%。许多研究小组不断发展的工作表明，参与修饰tau蛋白的基因，特别是那些调节tau蛋白磷酸化的基因，是导致AD和FTD遗传风险的诱人候选者。在病理或遗传基础上未发现tau异常的情况下，涉及蛋白质加工的关键机制失调

DESCRIPTION (provided by applicant): The identification of the genetic bases of dementias remains an important goal of research whose aims are to improve our understanding and develop new therapeutics for these diseases. The discovery of tau mutations in inherited cases of frontotemporal dementia (FTD) demonstrated that tau dysregulation can cause neurodegenerative disease. But, tau mutations have not been described in AD, and tau mutations account for about 15% of familial FTD cases. An evolving body of work from many groups suggests that genes involved in modifying tau, especially those that modulate tau phosphorylation are enticing candidates for contributing to the genetic risk for these AD and FTD. In cases where tau abnormalities have not been identified on a pathological or genetic basis, dysregulation in key machinery involved in protein processing and folding apparatus may provide additional genetic risk elements. The goal of this proposal is to identify and confirm these novel genetic risk factors in Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) using a novel re-sequencing approach that allows massively parallel, cost-effective gene re-sequencing in patients recruited by a multi-center collaborative group of NIA funded ADCs, fully consistent with the stated RFA goals. This approach will allow a tour de force assessment of the hypothesis that these pathways that have been implicated in neurodegenerative disease, and for whom there is a strong underlying biological and pathophysiological rationale are involved, rather than simply testing one gene at a time. Some of these studies will be completed in understudied ethnic minorities, providing important data on sequence variants in populations that have not been studied in this detail and for whom such data is typically not yet available in public or commercial databases. The biomaterials and clinical data from these patients, along with the genetic data obtained will be deposited with the NACC and NCRAD, thus providing an invaluable genetic resource. This data will be integrated with other potential SNPs in a larger set of cases and controls, so as to make maximum use of haplotype information. Association studies will be performed to identify disease-associated variants in FTD and in each ethnic cohort of AD subjects, so as to identify any population specific risk variants that can provide important data that will serve as the foundation for future studies in these groups.