Cerebrospinal Fluid Aβ42/40 Corresponds Better Than Aβ42 to Amyloid PET in Alzheimer's Disease

J Alzheimers Dis. 2017;55(2):813-822. doi: 10.3233/JAD-160722.

Abstract

Background: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone.

Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results.

Methods: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions.

Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases.

Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

Keywords: Alzheimer’s disease; amyloid-β; biomarker; cerebrospinal fluid; positron emission tomography.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / genetics
  • Amyloid / metabolism*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Aniline Compounds / metabolism
  • Apolipoprotein E4 / genetics
  • Female
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid*
  • Positron-Emission Tomography*
  • Thiazoles / metabolism

Substances

  • 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
  • Amyloid
  • Amyloid beta-Peptides
  • Aniline Compounds
  • Apolipoprotein E4
  • Peptide Fragments
  • Thiazoles
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)