Genetics of Alzheimer's disease--routes to the pathophysiology.

Considerable advances have been made the last years in the understanding of the pathogenesis of Alzheimer's disease (AD): Several pathogenic mutations have been found in the amyloid precursor protein gene on chromosome 21. Two other dominantly operating genes on chromosome 14 and 1 were recently cloned, named presenilin 1 and 2, respectively. Mutations in these genes give rise to AD with a very early age of onset. Increased Abeta1-42 is most likely the pathogenic mechanism in all these cases. A susceptibility gene for AD has also been found. There is an association between the epsilon4 allele of the apolipoprotein E (APOE) gene and late-onset AD. The epsilon4 allele increases the risk for AD, although some epsilon4 homozygotes may live a long life without developing AD. The mechanism by which APOE epsilon4 promotes development of AD is most likely increased plaque formation. The new knowledge on pathogenic mechanisms of the disease gives opportunities for alternative strategies for therapeutic intervention.