Physical Mapping of the Familial AD Region of Chromosome 21

           Alzheimer’s disease is becoming an increasingly important public health problem as the American population ages. It has a devastating impact on the individual, his family and society in general. There is no cure for the disorder, and no effective means of slowing its progression. It has not been possible to develop a treatment aimed at blocking the cause of AD because no one knows for sure what the root cause of the disease is. It had been noted for some years that there might be some inheritance of AD since it tended in some cases to run in families . In fact, in a few families the disease seems to be inherited in a very clear-cut traceable way and has therefore been termed familial Alzheimer’s disease (FAD). In these families at least, the cause of the disease is clear. It is a defective gene inherited as a “dominant”, meaning that a single copy of the disease gene can cause the disorder. The goal of our research is to purify this gene and to study its normal structure as well as the things that go wrong with it in FAD. Once the right gene has been found, we will have in hand the actual cause of one form of AD. This knowledge could well lead us to the causes of sporadic AD cases, and might provide the necessary information to design a treatment aimed specifically at blocking the effects of the disease gene.            Two years ago, we discovered that in at least some families the defective ge ne that causes familial Alzheimer disease is located on chromosome 21, the same chromosome involved in Down syndrome. Ye developed firm evidence that the culprit gene is located in a segment of the chromosome that might contain up to 100 other genes. In the past grant period we began to construct a map of the DNA in this stretch of chromosome to aid in searching for the specific gene that goes wrong in FAD. The need for a map of the string of DNA, with firmly placed spots of known location is the same for the geneticist as the need for the rally driver to have a clear roadmap with known cities, towns and other landmarks. Having a map helps one to get around an area with a minimum of effort and prevents one from getting lost. For the FAD region of chromosome 21, about 60% of the map has been now been charted and several recognizable landmarks have been firmly positioned. Ye had hoped that the change in the FAD gene that causes the disease might also cause a visible change in the map, but so far there is no obvious difference in the structure of the map in normal or affected people that can lead us directly to the gene that causes FAD                     In the coming grant period, we want to complete the remainder of the map still looking for some visible difference in structure that would signal the precise spot containing the genetic defect . We plan to also use the reverse strategy , by examining the DNA of several people who are already known to have structural changes in this stretch of chromosome and have AD. Ye will find out whether the DNA changes that have occurred in these people have damaged the AD gene by examining the genes close to the spot where the DNA has been altered. Finally, if finishing the map and studying these unique AD patients has not led us to the culprit gene in FAD, we plan to use the map as a guide for sorting one by one through the genes that are in the FAD region until we find the precise one that causes the disorder.?                 The long – term goals of this work are to determine how the gene that we find to be damaged actually triggers the disease . This information is essential if we are to design a specific treatment since it will tell us what biochemical change we are trying to treat. While the gene that we find may only cause AD in a small fraction of cases, it is also possible that some altered form of the gene is at the root of AD in a high proportion of patients . Furthermore, the FAD form of the disorder is the only type of AD for which a plan can be put on paper to get to the cause of the disease. We are very hopeful that knowing how the defective gene on chromosome 21 can cause degeneration of the brain will give us clues to what other factors in the environment or what other genes might have the potential to do the same thing. The understanding we develop of the cause of FAD might consequently lead to a similar understanding for sporadic AD.