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

Nat Commun. 2019 May 20;10(1):2240. doi: 10.1038/s41467-019-10152-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / pathology*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism
  • Brain / pathology
  • Cell Line, Tumor
  • Cognitive Dysfunction / cerebrospinal fluid
  • Cognitive Dysfunction / pathology*
  • Cohort Studies
  • Disease Progression
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid
  • Peptide Fragments / metabolism*
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley


  • Amyloid beta-Peptides
  • Biomarkers
  • Peptide Fragments
  • amyloid beta-protein (1-34)
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse