Chromosome 14 and Alzheimer's Disease

Alzheimer’s Disease (AD) is a common neurodegenerative disease for which no treatment or preventative measures are known. Those affected with AD eventually require total institutional care and invariably die from health conditions related to the disease. Over 3 million individuals are affected in the US at an annual cost of over $50 billion/year to the US economy. Although onset of the disease can occur as early as the 3rd decade of life, AD is most common in the elderly; perhaps as many as 10% of those over 65 and 50% of those over 85 have the disease. AD may be related to the normal aging process; autopsies of cognitively normal elderly persons have the neuropathologic features of AD (amyloid plaques, neurofibrillary tangles) at a much lower density. Therefore, studies of AD are important for both solving the disease and for better understanding the process of normal aging.

The inheritance of defective genes causes at least some cases of AD. Numerous large families in which AD appears to be inherited have been described in the scientific literature. Three chromosomal locations have been identified which contain genes which, when defective, cause AD. One is the APP gene on chromosome 21; mutations in this gene are responsible for a form of early-onset FAD. The second location ·is on chromosome 19; mutations in an as yet unidentified gene in this region possibly cause some forms of late-onset AD. Recently, we found that a region on chromosome 14 contains a gene capable of causing another form of early-onset FAD. Still other as yet unidentified genes at other locations may be responsible for FAD.

The basic hypothesis of this grant is that a gene on chromosome 14 is responsible for one form of AD. This gene, when defective, is involved in one of the key steps leading to AD. Identification of this gene will contribute to the understanding of the basic case of AD.

The specific aim of this proposal is to use genetic methods to identify the chromosome 14 FAD gene. Each person has 2 copies of each chromosome including chromosome 14. We will isolate single copies of chromosome 14 from subjects in AD families using genetic methods which can be performed in the laboratory. Being able to isolate individual chromosomes will greatly facilitate narrowing the region of chromosome 14 which contains the AD gene. We will also isolate the segment of chromosome 14 containing the AD gene using the same methods. This approach will facilitate the eventual cloning of the chromosome 14 gene.

The long term goal is to clone the chromosome 14 gene. Once cloned it will be possible to identify the normal function of the protein coded for by the gene. Once mutations are identified, it will be possible to determine what role the abnormal gene and protein play in the development of the disease. Identification of the chromosome 14 gene will provide key information about the basic mechanism of AD development. Also, knowing what proteins are involved in AD could lead to the rational design of treatments or preventative measures for AD.

Grantee institution at the time of this grant: University of Washington