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More than 5 million Americans have Alzheimer disease, and a subset of these cases is due to genetic disorders. This includes familial Alzheimer disease, caused by mutations in the presenilin-1 and presenilin-2 genes.[1]

The most popular theory behind the neuropathology of familial Alzheimer disease is the amyloid cascade hypothesis. This hypothesis states that beta-secretase first cleaves the amyloid precursor protein. The amyloid precursor protein is thought to be further cleaved via the carboxypeptidase activity of gamma-secretase by cutting every 3 amino acids to form amyloid-beta peptides of different lengths. Most of the product produced is amyloid-beta 40, which contains 40 amino acids. The minor product is amyloid-beta 42, which contains 42 amino acids and is hydrophobic and insoluble. A situation where a mutation causes a change in the ratio of product produced, specifically an increase in amyloid-beta 42 production, can lead to amyloid-beta aggregation and deposition. This excessive amyloid-beta deposition and intracellular neurofibrillary tangles of tau protein can damage DNA and RNA in neural cells.[7][8] Experiments with mutant presenilin-1-containing gamma-secretase complexes, as seen with familial Alzheimer disease, have suggested that the mutations can lead to an altered gamma-secretase complex. This alteration causes altered positioning of substrates for proteolysis and can lead to increased production of insoluble amyloid-beta 42 and decreased production of amyloid-beta 40. Increased levels of insoluble amyloid-beta 42 have also been seen in postmortem studies in those affected by presenilin-1 and presenilin-2 mutations compared to those with sporadic Alzheimer disease. This altered production increases the amyloid-beta 42 to 40 ratio, increasing the possibility of toxic amyloid-beta aggregation.[6][9]