This project is designed to be integrated into the genetic studies that have been developed as part of the Duke Alzheimer's Disease Research Center (ADRC) and will use sib-pair linkage analysis to investigate a genetic etiologic hypothesis of Alzheimer's Disease (AD). This proposal requests support for the applicant to (1 ascertain, develop, and longitudinally follow a subset of families at particular genetic risk for the development of AD; (2) to obtain blood samples suitable for DNA banking, lymphoblast transformation, DNA analysis and RFLP screening; and (3) to assess genetic linkage data by the implementation of the Haseman and Elston sib-pair method. Target families for ascertainment include those with at least two affected members who meet clinical or pathological criteria for late onset (greater than age 60) AD. Available """"""""at- risk"""""""" family members of the proband will be evaluated, initially with field screening instruments, and subsequently with complete neurologic and cognitive evaluation if appropriate. Longitudinal surveillance will be done to detect new cases of dementia. Appropriate blood samples for lymphoblastic DNA cell lines will be obtained; subsequently, DNA analysis and RFLP screening will be performed. Sib-pair data analysis, particularly useful where the underlying genetic mechanism is unknown, will be used to identify promising linkage relationships. Standard likelihood (LOD score) methods will then be used to estimate linkage parameters and address the possibility of genetic heterogeneity. This proposal is designed to develop the applicant's competence in the scientific investigation of AD by providing training in pedigree development and analysis, molecular genetic techniques and sib-pair methods of analysis. Combined with her previous clinical training, the skills obtained through the implementation of this proposal will facilitate the applicant's development into a successful independent investigator.
