Current state of Alzheimer’s fluid biomarkers
Open accessAbstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.
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CSF interacts directly with the CNS extracellular space and can offer a representative picture of CNS pathologies.
“CSF biomarkers are used because CSF interacts directly with the CNS extracellular space and can thus offer a representative picture of CNS pathologies. 4”
From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [4]
The across-tissue correlation for YKL-40 was not affected by disease status.
“and the across‐tissue correlation for YKL‐40 was not affected by disease status. 4”
From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [4]
The Inflammation/glial activation section discusses YKL-40 levels in CSF and plasma, but does not report a correlation between the two or test whether disease status affects it. Searches for the across-tissue correlation and for a CSF–plasma YKL-40 correlation found no passage addressing that claim. (LLM, conf=0.73)
Experimental — accuracy not yet measuredThis underrepresentation likely reflects neuronal loss in Alzheimer's disease and is consistent with NEFL as a cerebrospinal fluid biomarker.
“likely reflecting neuronal loss associated with AD and consistent with NEFL being identified as an AD biomarker in the cerebrospinal fluid (CSF)26”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [26]
SORL1 polymorphisms have been linked to Alzheimer's disease susceptibility, and CHI3L1 is a prognostic fluid biomarker for preclinical Alzheimer's disease.
“SORL1 polymorphisms have been linked to susceptibility to AD28 and CHI3L1 is a prognostic fluid biomarker for preclinical AD26”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [26]
BACE1 biomarkers are associated with other core CSF and neuroimaging AD biomarkers and with APOE ε4 allele presence.
“Some studies also showed an association between BACE1 biomarkers and other core CSF and neuroimaging biomarkers of AD as well as the presence of apolipoprotein E (APOE) ε4 allele (79–85).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [85]
CSF BACE1 concentration and activity have good diagnostic performance in discriminating AD dementia, MCI, and cognitively healthy individuals.
“During the past 15 years, a few human in vivo studies reported good diagnostic performance of CSF BACE1 concentration (supposed to reflect gene expression levels) and activity in discriminating among patients with AD dementia, patients with MCI, and cognitively healthy individuals (79–85).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [85]
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References 405 · Cited by 518
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- Authors
- Molinuevo, J. L., Ayton, S., Batrla, R., Bednar, M. M., Bittner, T., Cummings, J., Fagan, A. M., Hampel, H., Mielke, M. M., Mikulskis, A., O’Bryant, S., Scheltens, P., Sevigny, J., Shaw, L. M., Soares, H. D., Tong, G., Trojanowski, J. Q., Zetterberg, H., & Blennow, K.
- Affiliations
- The University of Melbourne (AU)
- F. Hoffmann-La Roche AG (CH)
- Takeda (United States) (US)
- Cleveland Clinic (US)
- Washington University in St. Louis (US)
- Centre National de la Recherche Scientifique (FR)
- Mayo Clinic (US)
- Biogen (United States) (US)
- University of North Texas Health Science Center (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Pennsylvania (US)
- AbbVie (United States) (US)
- Lundbeck (United States) (US)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Blennow, Kaj
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2018-11-28
- Volume
- 136
- Issue
- 6
- Pages
- 821-853
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6280827
- OpenAlex
- W2902155257
- Cited by
- 518
- References
- 405
- Citations by year
- 2026: 27 · 2025: 48 · 2024: 57 · 2023: 69 · 2022: 59 · 2021: 115 · 2020: 85 · 2019: 58
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- HAL (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Roche Diagnostics International
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, fluid biomarkers, cerebrospinal fluid biomarkers, blood biomarkers, amyloid-beta 42, tau phosphorylation, total tau, context of use, disease-modifying therapy, BACE1, TREM2, YKL-40, CXCL10, neurogranin, SNAP-25, synaptotagmin, alpha-synuclein, TDP-43, ferritin, VILIP-1, neurofilament light chain
- MeSH terms
- Alzheimer Disease, Humans, Biomarkers
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