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CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis
Open accessAbstract
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.
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“Notably, P-tau181 concentration is the most accurate indicator for differentiating AD from non-AD dementia.372,373”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [372]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The only disorder that consistently shows an increase in CSF P-tau is AD [143], whereas this biomarker is normal in other neurodegenerative disorders.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [143]
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In the citing paper
“Increased concentrations of extracellular soluble phosphorylated tau (p-tau) and total tau (t-tau) constitute a reliable index of this intracellular process in mild cognitive impairment due to AD2,3 and AD dementia.2,4”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [2]
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In the citing paper
“The most thoroughly examined P-tau epitope as a CSF biomarker for AD is threonine 181 (P-tau181) [143], but assays for the concentration of P-tau231 and P-tau199 correlate tightly with P-tau181 and show very similar diagnostic accuracy [144].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [143]
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In the citing paper
“CSF tau levels are not increased in non-AD tauopathies57–60, suggesting that extracellular tau is not a primary target in these conditions.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [59]
Experimental — accuracy not yet measured
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The only disorder that consistently shows an increase in CSF P-tau is AD [143], whereas this biomarker is normal in other neurodegenerative disorders.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [143]
Experimental — accuracy not yet measuredIn the citing paper
“A recent meta-analysis confirmed elevated levels of YKL-40 in AD dementia, although the association with AD was moderate compared with the core CSF AD biomarkers Aβ42, t-tau, and p-tau.25”
From CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease (2018) · cites this paper as [25]
In the citing paper
“along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [218]
In the citing paper
“CSF tau levels are not increased in non-AD tauopathies57–60, suggesting that extracellular tau is not a primary target in these conditions.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [59]
In the citing paper
“Of note, CSF tau levels are increased in AD but not in the other tauopathies57–60, suggesting that extracellular spread of tau pathology is not a prominent feature of non-AD tauopathies.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [59]
In the citing paper
“reduced concentrations of Aβ42 in CSF and increased retention of Aβ tracers in the brain have been considered as early biomarkers of AD.255–258”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [255]
In the citing paper
“Attempts to discover new biomarkers for the diagnosis of early stages of the disease are ongoing [134–136].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [135]
In the citing paper
“CHI3L1, which encodes YKL-40 protein, is expressed in astrocytes and is a biomarker of inflammation in Alzheimer’s disease [48]”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [48]
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Metadata
- Authors
- Olsson, B., Lautner, R., Andreasson, U., Öhrfelt, A., Portelius, E., Bjerke, M., Hölttä, M., Rosén, C., Olsson, C., Strobel, G., Wu, E., Dakin, K., Petzold, M., Blennow, K., & Zetterberg, H.
- Affiliations
- University of Gothenburg (SE)
- University of Antwerp (BE)
- Alzforum (US)
- University of the Witwatersrand (ZA)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Olsson, Bob
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 15
- Issue
- 7
- Pages
- 673-684
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W2327547544
- Cited by
- 2,049
- References
- 35
- Citations by year
- 2026: 123 · 2025: 200 · 2024: 243 · 2023: 214 · 2022: 240 · 2021: 253 · 2020: 228 · 2019: 198 · 2018: 188 · 2017: 114 · 2016: 42
- FWCI
- 25.79
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Chalmers Publication Library (Chalmers University of Technology) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- H2020 European Research Council (681712)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, biomarkers, cerebrospinal fluid biomarkers, blood biomarkers, amyloid-beta 42, tau protein, phosphorylated tau, neurofilament light chain, neurotensin, APP metabolism, blood-brain barrier, YKL-40, glial activation, mild cognitive impairment, diagnostic accuracy, early diagnosis, neurodegeneration, amyloid plaques
- MeSH terms
- Alzheimer Disease, Humans, Biomarkers
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