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. Tw o other dominantly operating genes on chromosome 14 and 1 were recently clo ned, named presenilin 1 and 2, respectively. Mutations in these genes give rise to AD with a very early age of onset. Increased A beta 1-42 is most li kely the pathogenic mechanism in all these cases. A susceptibility gene for AD has also been found. There is an association between the epsilon 4 alle le of the apolipoprotein E (APOE) gene and late-onset AD. The epsilon 4 all ele increases the risk for ADI although some epsilon 4 homozygotes may live a long life without developing AD. The mechanism by which APOE epsilon 4 p romotes development of AD is most likely increased plaque formation. The ne w knowledge on pathogenic mechanisms of the disease gives opportunities for alternative strategies for therapeutic intervention.