CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

doi:10.1016/S1474-4422(16)00070-3

The Lancet Neurology

Volume 15, Issue 7, June 2016, Pages 673-684

https://doi.org/10.1016/S1474-4422(16)00070-3 Get rights and content

Summary

Background

Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease.

Methods

In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aβ42, Aβ40, Aβ38, sAPPα, and sAPPβ), tangle pathology (P-tau), blood–brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline.

Findings

Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44–2·64, p<0·0001), P-tau (1·88, 1·79–1·97, p<0·0001), and Aβ42 (0·56, 0·55–0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aβ42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90–2·91, p<0·0001) and plasma T-tau (1·95, 1·12–3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28–1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples.

Interpretation

The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aβ42 and Aβ40 were not. Due to their consistency, T-tau, P-tau, Aβ42, and NFL in CSF should be used in clinical practice and clinical research.

Funding

Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.

Introduction

Worldwide, Alzheimer's disease is the most common of the neurodegenerative diseases. Neuropathological hallmarks include amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles throughout the brain.¹ However, several drug candidates targeting Aβ have not been successful in large, multicentre clinical trials, and it is now generally acknowledged that this is partly because a large proportion of clinically diagnosed patients show no evidence of amyloid pathology on PET scans, and thus do not have Alzheimer's disease.² The inclusion of falsely diagnosed patients in clinical trials reduces the possibility of identifying a clinical benefit of the tested drug and points to the need for validated biomarkers in drug development and clinical practice.

During the past 25 years, three core CSF biomarkers for Alzheimer's disease have been identified and tested in hundreds of studies. These are the 42-aminoacid form of Aβ (Aβ42), which is found at low concentrations in patients with Alzheimer's disease due to cortical amyloid deposition, total tau (T-tau) at high concentrations due to cortical neuronal loss,3, 4, 5, 6 and phosphorylated tau (P-tau) at high concentrations, reflecting cortical tangle formation.7, 8 High diagnostic accuracy of these biomarkers has been shown for Alzheimer's disease, with sensitivity and specificity reaching 85–90%, and also in patients at the mild cognitive impairment stage of the disease.⁹ Subsequently, these biomarkers have been incorporated into modern diagnostic research criteria.¹⁰ However, individual studies of biomarker validity vary greatly and no comprehensive meta-analysis has assessed their diagnostic performance. Nor has one been done of emerging biomarkers reflecting neurodegeneration, glial cell activation, and amyloid precursor protein (APP) metabolism, which show promise as diagnostic tools.¹¹

We examined the scientific literature for the 15 most promising biomarkers in both CSF and blood, including established Alzheimer's disease biomarkers and other markers of neurodegeneration, glial and blood–brain-barrier function, and APP metabolism, to establish which ones can be used to distinguish patients with Alzheimer's disease from controls, and patients with mild cognitive impairment due to Alzheimer's disease from those with stable mild cognitive impairment.

Section snippets

Search strategy and selection criteria

We did this systematic review and meta-analysis according to the PRISMA guidelines.¹² We searched PubMed and Web of Science for articles published in English between July 1, 1984 (when the first diagnostic criteria were published)¹³ and June 30, 2014, which reported data for biomarkers of neurodegeneration (T-tau,3, 4, 5, 6 neurofilament light protein [NFL],¹⁴ neuron-specific enolase [NSE],¹⁵ visinin-like protein 1 [VLP-1],¹⁶ and heart fatty acid binding protein [HFABP]¹⁷), APP metabolism

Results

We identified 4521 articles from the initial PubMed screen and 3500 remained after removal of duplicates. We then added 624 articles identified from Web of Science that did not have a PubMed identification number and were therefore not identified by the PubMed search. 585 full-text articles were assessed for eligibility, and 231 articles were included in the systematic review and meta-analyses (figure 1). From the results of the quality assessment, five articles were classified as high quality

Discussion

Our study provides the most comprehensive meta-analysis of the rapidly growing biomarker literature in Alzheimer's disease and mild cognitive impairment. It shows unequivocally that Alzheimer's disease is associated with lower CSF levels of Aβ42 and higher CSF levels of T-tau and P-tau compared with controls. Furthermore, Alzheimer's disease is associated with increased CSF levels of NFL, NSE, VLP-1, HFABP, and YKL-40, and increased plasma levels of T-tau.

Fluid biomarker measurement in

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ArticlesCSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Search strategy and selection criteria

Results

Discussion

Lancet

Neurobiol Aging

Neurosci Lett

Biol Psychiatry

Am J Pathol

Prog Neurobiol

Alzheimers Dement

Control Clin Trials

Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease

N Engl J Med

Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

Arch Neurol

Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury

Neurology

CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease

Brain

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings

Neurology

Cerebrospinal fluid and plasma biomarkers in Alzheimer disease

Nat Rev Neurol

New criteria for Alzheimer's disease: which, when and why?

Brain

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

BMJ

Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

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Articles
CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis