GENETIC-HETEROGENEITY OF GENE DEFECTS RESPONSIBLE FOR FAMILIAL ALZHEIMER-DISEASE

Inherited Alzheimer's disease is a genetically heterogeneous disorder that involves gene defects on at least five chromosomal loci. Three of these loci have been found by genetic linkage studies to reside on ch romosomes 21, 19, and 14. On chromosomes 21, the gene encoding the pre cursor protein of Alzheimer-associated amyloid (APP) has been shown to contain several mutations in exons 16 and 17 which account for roughl y 2-3 % of familial Alzheimer's disease (FAD). The other loci include what appears to be a susceptibility gene on chromosome 19 associated w ith late-onset (> 65 years) FAD, and a major early-onset FAD gene defe ct on the long arm of chromosome 14. In other early- and late-onset FA D kindreds, the gene defects involved do not appear to be linked to an y of these three loci, indicating the existence of additional and as o f yet unlocalized FAD genes. This review provides a historical perspec tive of the search for FAD gene defects and summarizes the progress ma de in world-wide attempts to isolate and characterize the genes respon sible for this disorder.