Core F: Genetics SUMMARY During the last two decades three 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. Several of the most promising new therapeutics are based on the Aß hypothesis, a hypothesis strongly supported by the causative mechanisms of disease mutations in autosomal dominant families. As these putative therapeutics are tested in clinical trials there is a growing need to use the ADAD kindreds both to understand the natural history of the earliest clinical and preclinical phases of the disease and to test the efficacy of the therapeutics in a setting, where if the Aβ hypothesis is correct, they should have a dramatic effect on prognosis. During the last funding cycle, we have expanded our network of centers and have begun longitudinal characterization of a large series of ADAD kindreds with known disease-causing mutations. The goal of the next funding period will be to continue longitudinal follow up of these kindreds to identify the earliest detectable changes associated with development of disease and to characterize the temporal series of events that occurs up to and including the diagnosis of symptomatic AD. The goal of the Genetics Core of the DIAN initiative is to provide genetic information and useful biological and genomic materials to the research community for the study of AD. We have already collected genomic samples from 531 individuals and generated fibroblasts from 99 individuals. We anticipate collection of an additional 125 new individuals during the next funding cycle, including participants from NIH and self-funded sites. We will expand the fibroblast and induced pluripotent stem cell collection. The Core will maintain and curate a list of pathogenic mutations and confirm that new DIAN families carry an ADAD mutation. The Core will also generate GWAS and APOE genotype data on all individuals and obtain biological materials (fibroblasts, induced pluripotent stem cells, white blood cells) to perform cell-based functional studies. All data will be placed in the DIAN database. We will support all projects in DIAN and perform analyses with other Cores to identify novel factors modulating age at onset in these families.