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  • Review Article
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Cerebrospinal fluid and plasma biomarkers in Alzheimer disease

Abstract

Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-β immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-β. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.

Key Points

  • Current clinical diagnostic criteria for Alzheimer disease (AD) require a patient to have dementia before a diagnosis can be made, and are largely based on the exclusion of other disorders

  • Disease-modifying drugs for AD, when they become available, will need to be administered very early in the course of the disease, before neurodegeneration is too severe and widespread

  • No clinical method is available for identifying prodromal AD in patients with mild cognitive impairment (MCI), as such individuals have only mild disturbances in episodic memory

  • The cerebrospinal fluid (CSF) biomarkers total tau, phosphorylated tau (p-tau181 and p-tau231) and β-amyloid1–42 have a high diagnostic accuracy for AD, and for prodromal AD in patients with MCI

  • CSF biomarkers are increasingly being used in the clinic for diagnosing AD, and will also be valuable in clinical trials, allowing enrichment of patient populations with pure AD cases

  • Biomarker evidence that a candidate drug affects the central disease processes in AD will, together with a beneficial effect on cognition, be essential for labeling the drug as disease modifying

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Figure 1: Metabolic pathways for the generation of APP fragments detected in the CSF.
Figure 2: Tau isoforms and phosphorylation sites.
Figure 3: The amyloid cascade hypothesis of AD.
Figure 4: Evaluation of Alzheimer disease therapies by cognitive scales.

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Correspondence to Kaj Blennow.

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Competing interests

K. Blennow and M. Weiner have received research support from Innogenetics. H. Hampel has acted as a consultant for and received research support from BRAHMS AG. He also holds a patent with this company. H. Zetterberg declares no competing interests.

Supplementary information

Supplementary Figure 1

Lumbar puncture with the patient in the sitting position (DOC 1791 kb)

Supplementary Figure 2

CSF biomarkers for Alzheimer disease (DOC 607 kb)

Supplementary Figure 3

Intrathecal immunoglobulin production (DOC 1567 kb)

Supplementary Table 1

Flow chart for LP and CSF biomarker analyses (DOC 44 kb)

Supplementary Table 2

Criteria for an ideal biomarker for AD (DOC 53 kb)

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Blennow, K., Hampel, H., Weiner, M. et al. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6, 131–144 (2010). https://doi.org/10.1038/nrneurol.2010.4

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