GENETIC AND MOLECULAR ADVANCES IN ALZHEIMERS-DISEASE

The abnormal deposition of amyloid beta protein (Abeta) in the brain is the major neuropathological characteristic of Alzheimer's disease (AD). The disease in some early-onset familial cases develops as a result of mutations in the gene coding for the beta-amyloid precursor protein (betaAPP) and in the majority of the rest appears to be caused by an unidentified gene on chromosome 14. Only one of the betaAPP gene mutations has been associated with aberrant betaAPP processing, resulting in an excess production of Abeta in vitro, a result suggesting that there might be excessive Abeta cleavage from betaAPP in AD in vivo. By contrast with the betaAPP mutants, no particular allele of the apolipoprotein E (APOE) gene Predicts the disease completely but one allele is associated with the disease suggesting APOE is a risk locus for AD. This discovery has been linked to increased deposition of Abeta in those cases carrying the risk allele. However, the genetic evidence is currently not sufficient to indicate whether betaAPP mismetabolism, direct or indirect Abeta neurotoxicity or dysfunction of betaAPP (or its derivatives) are central to the AD process.