Alzheimer's Disease (AD) is a common neurodegenerative disease for which no treatment or preventative measure exist. Affected individuals eventually require institutional care and invariably die from disease-related conditions. Over 3 million individuals are affected in the US at an annual cost of over $50 billion/year. Although onset can occur as early as the 3rd decade of life, AD is a disease of the elderly; as many as 10% of those over 65 yrs and 50% of those over 85 yr have AD. AD may be related to athe normal aging; autopsies of cognitively normal elderly persons show a low density of amyloid plaques, neurofibrillary tangles, features characteristic of AD. Therefore, studies of AD are important for both solving the disease and for better understanding normal aging. Defective genes are responsible for AD in some families. One AD gene is the amyloid precursor gene (APP) on chromosome 21. APP mutations cause autosomal dominant familial AD (FAD) in some early-onset kindreds. However, in the majority of early-onset families (90-95%) and in late-onset families, FAD is not caused by APP mutations. We used linkage analysis to identify an early-onset FAD locus on chromosome 14. This locus accounts for FAD in most of the early-onset kindreds which do not have APP mutations. We propose to identifying and clone the chromosome 14 gene using positional cloning techniques. Polymorphic markers will be identified for this region and mapped using the CEPH panel. These markers will be used to refine the position of the chromosome 14 FAD locus by linkage analysis. We will generate a radiation hybrid cell panel and a pulse field gel electrophoresis physical map of the FAD region for fine- scale mapping. Once the location has been refined, the corresponding DNA will be cloned, primarily using YAC clones, and a contig assembled. Genes in this contig will be identified and screened by DNA sequence analysis for FAD mutations. Once identified, the gene's function will be sought to understand its role in AD pathogenesis and possibly normal aging. Identification of the chromosome 14 gene may also help resolve the role of genes in late-onset AD.
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