Paul Saftig, Peter Kunach, Randall J. Bateman, Wiesje M. van der Flier, Philip Scheltens, Judes Poirier, John C.S. Breitner, Pedro Rosa-Neto, Mark A. Hancock, Christoph Hock, Vivienne Engelschalt, Filip Liebsch, Adeola Shobo, Charlotte E. Teunissen, Irem Ulku, Gerhard Multhaup, Luka Kulic, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Neurology, APH - Personalized Medicine, APH - Methodology, Epidemiology and Data Science, University of Zurich, and Multhaup, Gerhard
The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples., Aβ34 is generated from degradation of Aβ40 and Aβ42 by β-secretase. Here, the authors show that Aβ34 is a marker for amyloid clearance and is elevated in the CSF of patients that go on to convert from mild cognitive impairment to Alzheimer’s disease, suggesting it may be a useful biomarker.