[Familial forms of Alzheimer's disease]

TWO SITUATIONS: Familial occurrence of Alzheimer disease is observed in two quite different situations. The more common is the familial aggregation caused by the Apo E4 genotype. Nevertheless, APO E4 as a major risk factor is neither sufficient nor necessary to induce Alzheimer disease. The second possibility are the autosomal dominant forms of Alzheimer disease. Three different genes are concerned. MUTATIONS: The more frequent mutations are found in the Presenilin 1 gene (PS1), mutations in the amyloid precursor protein (APP) are rare and only a few Presenilin 2 gene (PS2) mutations are reported.

The main clinical characteristic of these autosomal dominant forms is an early age of onset below 60. Neuropathology is similar to sporadic cases: senile plaques with A beta peptide as a major component and neurofibrillary tangles containing Tau protein.

The demonstration that both APP, PS1, and PS2 gene mutations enhance the processing of APP to form A beta peptide is a major argument supporting the amyloid hypothesis of Alzheimer disease. This better knowledge of APP and PS1,2 processing and their interactions with binding proteins does permit to develop treatment strategies.