Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

Background: Alzheimer’s disease (AD) is associated with deposition of amyloid b (Ab) in the brain, which is reflected by low concentration of the Ab1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Ab peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Ab. Here, we test the hypothesis that AD is characterized by a specific CSF Ab 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 Ab isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FADassociated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Ab1-42 and high levels of Ab1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Ab1-42 and Ab1-16, but FAD mutation carriers exhibited very low levels of Ab1-37, Ab1-38 and Ab1-39. Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Ab isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Ab1-37, Ab1-38 and Ab1-39; fragments that are normally produced by g-secretase, suggesting that the PSEN1 A431E mutation modulates g-secretase cleavage site preference in a disease-promoting manner.