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.