Alzheimer disease is the leading cause of dementia in the elderly, affecting more than 4 million individuals in the U.S. alone. A genetic component has long been indicated in the etiology of the disease and has been supported in a number of genetic and epidemiological studies. Although some families show clear evidence of autosomal dominant inheritance, many others are equivocal, and thus the mode of inheritance of familial Alzheimer disease (FAD) is not well established. One gene for FAD has been identified (APP), but it accounts for less than 2% of FAD cases, and no other genes have yet been identified, although a location on chromosome 19 has been proposed. Through the efforts of the Human Genome Initiative, it is now possible to efficiently screen the entire genome for genes associated with FAD. The goal of the present proposal is to perform an efficient screen of the entire genome in order to identify all the major loci involved in FAD. Both early and late onset families will be incorporated into the screening process. A multicenter approach will be used to rapidly generate the necessary marker data, and to rapidly and efficiently perform the statistical analyses on these data. Since the emphasis of this proposal is on the analysis of the resulting data, only well-defined marker systems will be used and no effort will be expended to generate new markers. This approach will allow us to fully exploit the efforts of the Human Genome Initiative, thereby helping to fulfill its promise. A hierarchical structure for genotyping of the families will be established. Initially, a core set of families will be identified that have sufficient power to generate significant standard linkage results. Additional pedigrees with only a few affected individuals will be used for a variety of state of the art statistical methodologies including affected-pedigree-member (APM) analysis, sib-pair linkage studies as well as maximum likelihood methods inclusive of two locus models. Examination for and effects of heterogeneity and age of onset will also be incorporated into the study. The ultimate goal of the proposed research is the identification of all major loci involved in FAD etiology, as the first step in combatting this devastating disorder of the elderly.
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