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 chromosomes 21, 19, and 14. On chromosomes 21, the gene encoding the precursor protein of Alzheimer-associated amyloid (APP) has been shown to contain several mutations in exons 16 and 17 which account for roughly 2-3% of familial Alzheimer's disease (FAD). The other loci include what appears to be a susceptibility gene on chromosome 19 associated with late-onset (> 65 years) FAD, and a major early-onset FAD gene defect on the long arm of chromosome 14. In other early- and late-onset FAD kindreds, the gene defects involved do not appear to be linked to any of these three loci, indicating the existence of additional and as of yet unlocalized FAD genes. This review provides a historical perspective of the search for FAD gene defects and summarizes the progress made in world-wide attempts to isolate and characterize the genes responsible for this disorder.