Progress in molecular genetics of Alzheimer's disease

Recent intensive work has highlighted the genetic basis of several forms of Alzheimer's disease (AD). Mutations in the amyloid precursor protein gene on chromosome 21 can cause either an early-onset autosomal dominant AD or hereditary cerebral hemorrhage with amyloidosis. On chromosome 14, a second gene associated with 70 to 90% of early-onset familiar AD (FAD) was identified by positional cloning in 1995, Still other kindreds show no linkage to either chromosome 21 or chromosome 14; the third locus (on chromosome 1) was recently identified in affected descendants of a group of families known as the Volga Germans. In late-onset (age > 65 years) AD, the apolipoprotein E gene allele epsilon 4 on chromosome 19 has clearly been shown to be a risk factor for the development of AD and appears to modify the age of onset of the disease. The emerging picture is that AD is a genetically complex, heterogeneous disorder. Precisely how these genetic factors interact with each other and with other yet-to-be-identified genetic and nongenetic (environmental) factors to produce the clinical and pathologic findings in AD remains to be elucidated.