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Fluid biomarker-based molecular phenotyping of Alzheimer's disease patients in research and clinical settings

Journal article
Authors Kaj Blennow
Henrik Zetterberg
Published in Progress in Molecular Biology and Translational Science
Volume 168
Pages 3-23
ISSN 1877-1173
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 3-23
Language en
Keywords Amyloid, Biomarkers, Cerebrospinal fluid, Neurofilament, Neurogranin, Plasma, Serum, Tau
Subject categories Neurochemistry, Psychiatry


Alzheimer's disease (AD) is very difficult to diagnose on pure clinical grounds, especially in the earlier phases of the disease. At the same time, lessons from recent clinical trials suggest that treatments have to be initiated very early, to have a chance to show clinical efficacy. Therefore, biomarkers reflecting core AD pathophysiology have a key position in clinical trials and clinical management. The core AD cerebrospinal fluid (CSF) biomarker toolbox include amyloid β (Aβ42 and the Aβ42/40 ratio) reflecting brain amyloidosis, total tau (T-tau) reflecting neurodegeneration intensity, and phosphorylated tau (P-tau) that is related to tau pathology. These CSF biomarkers have very consistently been found to have high diagnostic accuracy, also in earlier disease stages. Importantly, CSF Aβ42 and Aβ42/40 ratio show excellent agreement with amyloid PET readouts, indicating that these biomarker tests can be used interchangeably. Intense collaborative standardization efforts have given Certified Reference Materials (CRMs) to harmonize assay formats for CSF Aβ42, the most central AD biomarker, and CRMs for Aβ40 are under development. The core AD biomarkers are today available on high-precision fully automated analytical platforms, which will serve to introduce uniform cut-off levels and enable the large-scale introduction of CSF biomarkers for routine disease diagnosis. Of novel biomarker candidates, synaptic proteins, such as the dendritic protein neurogranin, show promise as tools to monitor synaptic degeneration, an important aspect of AD pathophysiology. Recent studies show that the core AD biomarkers also can be measured in blood samples. Ultra-sensitive assays that allow for quantification of neuronal proteins, such as tau and neurofilament light (NFL) in blood samples. Further, plasma Aβ42 and Aβ42/40 show high concordance with brain amyloidosis evaluated by PET scans. In the future, blood biomarkers may have value as screening tools, especially to rule out patients without biomarker evidence of AD pathology. © 2019 Elsevier Inc.

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