Alzheimer's Disease and Chromosome 21

The cause of Alzheimer’s disease is presently unknown. This disease may be related at least in part to normal aging since the pathologic hallmarks of AD are also seen to a lesser degree in normal elderly. A large body of evidence ·indicates that at least some if not all AD cases are due to genetic factors which can be passed from one generation to the next. Pedigree analysis of families with multiple cases of presenile AD suggests an autosomal dominant gene(s) may be responsible for at least some occurrences of the disease. In these families, off· spring of affected persons appear to be at 50% risk of inheriting the FAD gene and developing AD. In other cases of AD, environmental factors (e.g. aluminum, head injury, toxic chemicals, etc) may be important and these factors may interact with faulty genes to cause AD. A combination of these factors may accelerate the aging process including early .development of AD. This grant application is designed to identify the gene or genes responsible for AD.

HYPOTHESIS

The basic hypothesis of this grant is that at least some forms of AD are the result of the inheritance of a defective gene. Genetic studies indicate that 1 of the possible genes causing AD is on chromosome 21, the same chromosome responsible for Downs syndrome. However, not all cases of inherited AD are caused by the same gene and there may be genes on other chromosomes which also can cause AD.

SPECIFIC AIMS

The specific aim of this proposal is to identify and clone the chromosome 21 gene responsible for inherited Alzheimer’s disease. To achieve this end we will first locate and characterize genes in a specific region of this chromosome. Then the genes identified will be scanned for the mutation responsible for AD. Once the chromosome 21 AD gene is identified, it will be used to search for similar genes on other chromosomes responsible for AD. Once all AD genes are cloned and identified, it may be possible to determine which cases of AD are the result of inherited factors. Identification of AD genes may also lead to determining the underlying cause of AD. Once the genes are fully characterized, it will be possible to determine what the gene product is, how it functions in the brain, and how a mutation in that gene can cause AD. Knowledge concerning the inherited form of the disease should help in understanding non-genetic forms of AD and how environmental factors influence the disease process.