Relationship between β-Secretase, inflammation and core cerebrospinal fluid biomarkers for Alzheimer's disease

J Alzheimers Dis. 2014;42(1):157-67. doi: 10.3233/JAD-140240.


Background: Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimer's disease (AD). The connection between these biomarkers remains unclear.

Objective: To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions.

Methods: We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers.

Results: CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients. CSF Aβ42 correlated positively with β-secretase activity (RS = 0.262) and sAβPPβ (RS = 0.341). CSF YKL-40 correlated positively with total tau (RS = 0.467) and p-tau (RS = 0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD.

Conclusions: CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.

Keywords: Alzheimer's disease; YKL-40; amyloid-β protein precursor; biological markers; cerebrospinal fluid; frontotemporal dementia; inflammation; β-secretase.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / cerebrospinal fluid*
  • Aged
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnosis
  • Amyloid Precursor Protein Secretases / cerebrospinal fluid*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Protein Precursor / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid
  • Chitinase-3-Like Protein 1
  • Cognition Disorders / cerebrospinal fluid
  • Cognition Disorders / diagnosis
  • Female
  • Frontotemporal Dementia / cerebrospinal fluid
  • Frontotemporal Dementia / diagnosis
  • Humans
  • Lectins / cerebrospinal fluid*
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid
  • Phosphorylation
  • Prospective Studies
  • Sensitivity and Specificity
  • tau Proteins / cerebrospinal fluid


  • APP protein, human
  • Adipokines
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Biomarkers
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • Lectins
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Amyloid Precursor Protein Secretases