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Portelius, Erik; Andreasson, Ulf; Ringman, John M.; Buerger, Katharina; Daborg, Jonny; Buchhave, Peder; Hansson, Oskar; Harmsen, Andreas; Gustavsson, Mikael K.; Hanse, Eric; Galasko, Douglas; Hampel, Harald; Blennow, Kaj; Zetterberg, Henrik (2010): Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. In: Molecular Neurodegeneration 5:2


Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results: We measured A beta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of A beta 1-42 and high levels of A beta 1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in A beta 1-42 and A beta 1-16, but FAD mutation carriers exhibited very low levels of A beta 1-37, A beta 1-38 and A beta 1-39. Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF A beta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of A beta 1-37, A beta 1-38 and A beta 1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.