Alzheimer's disease (AD) is the most common cause of irreversible, chronicdementia. Although AD may be familial in only one~third of all cases, the main justification for studying autosomal dominant cases lies in the accuracy of diagnosis which may be inferred through postmortem examination of other affected family members. More than 270 members of 23 pedigrees with an autosomal dominant form of AD have had skin fibroblast and peripheral blood lymphoblast cultures established. These cultures serve as a renewable source of DNA and cell lines for genetic linkage, viability, and biochemical studies. Recombinant DNA technology has been applied to perform genetic linkage studies in these families with inherited AD. Approximately 75% of the amyloid precursor protein (APP) gene has been sequenced in the Canadian and Italian pedigrees. The beta-amyloid peptide coding exons have been sequenced in 20 pedigrees. No mutations have been detected thus far. It appears that the Familial Alzheimer~s disease locus and APP gene on chromosome 21 reside at different locations in these pedigrees. With the departure of the PI (Dr. Polinsky) this project has been maintained mainly as a resource for future research to be developed in relation to a new Unit on Clinical Neurogenetics which has been established in the CNB. Inherited Alzheimer disease ~ longitudinal data collection, expansion of pedigree information and recruitment of additional family members, as well as counseling of numerous families, some followed since 1977, has continued. Collaborations have also continued although no patient was admitted during the year. In September 1993, we shall again admit families with the continued collaboration of Trey Sunderland, M.D., NIMH. Longitudinal study involves LP~s, PET, DNA, psychological testing, psychological and genetic counseling.