Allelic Association Studies in Chromosome 14 Linked AD

There is gene on chromosome 14 that carries a mutation (i.e sequence variation) which causes in some families early-onset Alzheimer disease. In these families children of an affected parent have a risk of 50% to inherit the genetic defect. If they have inherited the defective gene they will develop the disease later in life. The onset age of the disease is determined by the mean onset age of Alzheimer disease in their family and usually varies between 30 and 50 years in these chromosome 14 linked families. However, since the actual gene is not yet known we have no possibilities to predict if an at risk individual has or has not inherited the gene mutation. Although the chromosome location is known (band 14q24.3) the identification of the gene itself and the gene mutation has been hampered because of the large size of the candidate region that is comprising the gene. From our previous work we know that the region represents an approximate 3 to 6 million base pairs which stands for a few hundreds of genes. All these genes are potential candidate genes and should be analyzed for mutations. This would be an enormous task even now that new cloning techniques are available. Therefore, other methods should be tested that if successful would allow us to reduce the size of the candidate region to say 500.000 base pairs. Therefore, we propose to develop new genetic markers and test them in the chromosome linked Alzheimer disease families. Also, we have DNA of 2 large Belgian families that may have a common founder. If we, when using the new genetic markers, can identify markers that are shared between the 2 families we know that the disease gene must be close by and thus we would have reduced the candidate region substantially.

The identification of the chromosome 14 gene and gene mutation would mark an enormous progress in our understanding of the disease. It would tell us more about the biochemical pathway of the disease which may or may not have something to do with the amyloid deposition which seems to play an important role in the sequences leading to Alzheimer pathology in the brain. The knowledge about the chromosome 14 gene may also help us to develop a model system which would be extremely useful in the development of an effective therapy for the disease.