Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression

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 A beta peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of A beta 40 and A beta 42 into a common A beta 34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that A beta 34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, A beta 34 levels correlate with the overall A beta 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 A beta 34/A beta 42 ratio, representing A beta degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that A beta 34 represents a marker of amyloid clearance and may be helpful for the characterization of A beta turnover in clinical samples.