APP-derived peptides reflect neurodegeneration in frontotemporal dementia

Ann Clin Transl Neurol. 2019 Dec;6(12):2518-2530. doi: 10.1002/acn3.50948. Epub 2019 Dec 2.


Objective: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls.

Methods: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1-42, Aβ1-40, Aβ1-38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis.

Results: The CSF levels of Aβ1-40, Aβ1-38, and sAPPβ were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function.

Interpretation: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aβ1-42 levels are considered an indirect biomarker of cerebral amyloidosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Amyloid beta-Protein Precursor / cerebrospinal fluid
  • Female
  • Frontotemporal Lobar Degeneration / cerebrospinal fluid*
  • Frontotemporal Lobar Degeneration / diagnostic imaging
  • Frontotemporal Lobar Degeneration / pathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • amyloid beta-protein (1-42)