Alzheimer disease is the most common form of senile dementia with a prevalence of 1:5 in people over 80 years of age. Genetic factors are known to be involved in all forms of Alzheimer disease.
Variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and in the amyloid precursor protein gene (APP) lead to the autosomal dominant inherited hereditary early form of Alzheimer disease (onset of disease before the age of 60). In families with affected individuals in at least three generations, around 60% of cases are attributable to variants in the PSEN1 gene and around 20% to variants in the APP gene. Variants in the PSEN2 gene cause <5% of cases. For the remaining 15%, there are some indications of association with genes that have not yet been further characterized. PSEN1 and PSEN2 code for two of the four proteins which are part of the gamma-secretase protein complex. This complex is involved in the processing of the amyloid beta precursor protein to amyloid beta.
APP encodes the amyloid beta precursor protein, an ubiquitously expressed transmembrane protein. Variants in the PSEN1 or APP gene lead to an increase in amyloid beta 42 (Aβ42) at the expense of Aβ40. Both proteins are an essential component of neuritic plaques. However, the more hydrophobic Aβ42 aggregates more quickly to form toxic fibrils.
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