Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Alzheimer's Disease, early onset (AD1) [F00.0]

OMIM numbers: 104300, 104760 (APP), 607822, 104311 (PSEN1)

Dr. rer. nat. Christoph Marschall

Scientific Background

Alzheimer's disease, with a prevalence of 1:5 in patients over the age of 80, is the most frequently occurring form of senile dementia. Genetic factors are known to be involved in every form of Alzheimer’s disease.

Mutations in the presenilin-1 gene (PSEN1) and in the amyloid precursor protein gene (APP) are associated with the autosomal dominant hereditary early-onset form of Alzheimer's disease (onset before the 60th year of life). Approximately 65% of all cases are caused by mutations in the PSEN1 gene and approximately 15% by mutations in the APP gene. In <5% of all cases, mutations in the PSEN2 gene represent another cause of the disease. In the remaining approximately 15% of all cases, there are indications for associations with genes that have not been characterized yet. PSEN1 and PSEN2 encode two of the four proteins which are part of the gamma secretase protein complex. This complex is involved in processing the beta amyloid precursor protein into beta amyloid. APP encodes the beta amyloid precursor protein, an ubiquitously expressed, transmembrane protein. Mutations in the PSEN1 or APP gene lead to an increase in beta amyloid 42 (Aβ42) at the expense of Aβ40. Both proteins represent a crucial part of senile (neuritic) plaques. However, the more hydrophobic Aβ42 is more prone to aggregate to toxic fibrils.