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There are several familial forms of Alzheimer's disease (AD) most of whichare caused by mutations in the genes that encode the presenilin enzymes involvedin the production of amyloid-β (Aβ) from the amyloid precursor protein (APP).In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of thefibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-42)and it is now widely accepted that Aβ is related to the pathogenesis of AD andthat Aβ may both impair memory and be neurotoxic. In human cerebrospinal fluid(CSF) several C- and N-terminally truncated Aβ isoforms have been detected andtheir relative abundance pattern is thought to reflect the production and clearanceof Aβ. By using immunoprecipitation and mass spectrometry, we have previouslydemonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutationhave low CSF levels of C-terminally truncated Aβ isoforms shorter than Aβ1-40.Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139Tmutation may overexpress Aβ1-42 suggesting that this particular mutation may causeAD by stimulating γ-secretase-mediated cleavage at amino acid 42 in the Aβ sequence.

The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease