Identification of the Familial Alzheimer Locus

Alzheimer disease (AD) affects the health of more than two million people in the United States and touches the lives of many more Americans due to its severe emotional and financial impact on family members. AD is a degenerative disease of the central nervous system leading to a global loss of intellectual function with onset in adulthood and is the commonest form of dementia. Although the neuropathologic abnormalities of AD were described almost a century ago, the underlying biochemical defect has remained unknown. Recently, great progress in the search or the underlying abnormality has been made through the molecular genetic analysis of inherited forms of AD. These studies have led to the identification of chromosome 21 as the location for the familial AD gene. Although the precise location of an FAD gene has remained uncertain, the region close to the centromere has emerged as one of the most likely region s to contain a gene for AD. Until recently, despite intensive research, only a single DNA sequence has been defined in this region. This proposal describes new strategies designed to generate new DNA sequences and can dictate genes near the centromere. As a starting point we will use a novel DNA sequence that we recently discovered and mapped in the direct vicinity of the centromere and that itself may represent an expressed gene. Ye will also generate additional DNA sequences in this region by using the chromosomes from a rare patient we have identified. She carries a chromosome 21 that contains only the DNA close to the centromere in the region of the FAD gene. Th is chromosome therefore provides us with a very small slice of chromosome 21, eliminates the remainder and focuses our search for the gene on this region. The new DN A sequences will be characterized and used for the analysis of a family wit h AD that has a visible abnormality of chromosome 21. Because this chromosomal abnormality may be the cause of the AD in this family, we will begin to define their abnormality on the molecular (DNA) level, hoping this will identify the gene itself. Finally, the new DNA sequences defined in the region will be used to track the chromosome 21 gene responsible for Familial Alzheimer disease in three large families with early onset FAD. These studies will help close the gap leading to the isolation of the gene causing Alzheimer Disease.