CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum

Neurology. 2018 Oct 23;91(17):e1619-e1628. doi: 10.1212/WNL.0000000000006383. Epub 2018 Oct 5.


Objective: To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Methods: We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness.

Results: We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = -0.41, p < 0.001 and r = -0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions.

Conclusions: sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum.

Classification of evidence: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyloid beta-Protein Precursor / cerebrospinal fluid*
  • Amyotrophic Lateral Sclerosis / cerebrospinal fluid*
  • Amyotrophic Lateral Sclerosis / diagnostic imaging
  • Amyotrophic Lateral Sclerosis / genetics
  • Case-Control Studies
  • Chitinase-3-Like Protein 1 / cerebrospinal fluid*
  • Female
  • Frontotemporal Dementia / cerebrospinal fluid*
  • Frontotemporal Dementia / diagnostic imaging
  • Frontotemporal Dementia / genetics
  • Humans
  • Linear Models
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neurofilament Proteins / cerebrospinal fluid*
  • Neuropsychological Tests


  • Amyloid beta-Protein Precursor
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • Neurofilament Proteins
  • neurofilament protein L