Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography

JAMA Neurol. 2014 Oct;71(10):1282-9. doi: 10.1001/jamaneurol.2014.1358.


Importance: Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition.

Objectives: To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality.

Design, setting, and participants: This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38).

Exposures: Amyloid positron emission tomography imaging with 18F-flutemetamol.

Main outcomes and measures: Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples.

Results: The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE (apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = -0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = -0.32), memory function (r = -0.28), and hippocampal volume (r = -0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort.

Conclusions and relevance: Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / diagnostic imaging
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism*
  • Aniline Compounds
  • Benzothiazoles
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Cerebral Cortex / diagnostic imaging*
  • Cerebral Cortex / metabolism
  • Cognitive Dysfunction / cerebrospinal fluid*
  • Cognitive Dysfunction / diagnosis
  • Cognitive Dysfunction / diagnostic imaging
  • Cohort Studies
  • Cross-Sectional Studies
  • Early Diagnosis
  • Female
  • Gyrus Cinguli / diagnostic imaging*
  • Gyrus Cinguli / metabolism
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid*
  • Positron-Emission Tomography
  • Radiopharmaceuticals
  • Reproducibility of Results


  • Amyloid beta-Peptides
  • Aniline Compounds
  • Benzothiazoles
  • Peptide Fragments
  • Radiopharmaceuticals
  • amyloid beta-protein (1-42)
  • flutemetamol