Identification of the Familial Alzheimer locus

Alzheimer disease (AO) 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. AO 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 AO were described almost a century ago, the underlying biochemical defect has remained unknown. Recently, great progress in the search for the underlying abnormality has been made through the molecular genetic analysis of inherited forms of AO. These studies have led to the identification of chromosome 21 as the location for one gene and likely a second causing familial AO. Although the precise location of the second FAD gene has remained uncertain the region close to the centromere has emerged as one of the regions most likely to contain it. Until recently, despite intensive research, only a single ONA sequence has been defined in this region. This proposal describes new strategies designed to generate new ONA sequences and candidate genes near the centromere. As a starting point we will use a novel ONA sequence that we recently discovered and mapped in the direct vicinity of the centromere and that itself may represent an expressed gene. We will also generate additional ONA sequences in this region by using the chromosomes from a rare patient we have identified. She carries a chromosome 21 that contains the ONA close to the centromere in the region of the FAD gene. This 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 ONA sequences will be characterized and used for the analysis of a family with AO that has a visible abnormality of chromosome 21. Because this chromosomal abnormality may be the cause of the AO in this family, we will begin to define their abnormality on the molecular (ONA) level, hoping this will identify the gene itself. Finally, the new ONA 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.