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Acta Neuropathol. 2018 Dec;136(6):821-853. doi: 10.1007/s00401-018-1932-x. Epub 2018 Nov 28.

Current state of Alzheimer's fluid biomarkers.

Author information

1
BarcelonaBeta Brain Research Center, Fundació Pasqual Maragall, Universitat Pompeu Fabra, Barcelona, Spain.
2
Unidad de Alzheimer y otros trastornos cognitivos, Hospital Clinic-IDIBAPS, Barcelona, Spain.
3
Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
4
Roche Centralised and Point of Care Solutions, Roche Diagnostics International, Rotkreuz, Switzerland.
5
Neuroscience Therapeutic Area Unit, Takeda Development Centre Americas Ltd, Cambridge, MA, USA.
6
Genentech, A Member of the Roche Group, Basel, Switzerland.
7
Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
8
Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
9
AXA Research Fund and Sorbonne University Chair, Paris, France.
10
Sorbonne University, GRC No 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
11
Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France.
12
Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
13
Departments of Epidemiology and Neurology, Mayo Clinic, Rochester, MN, USA.
14
Biomarkers, Biogen, Cambridge, MA, USA.
15
Department of Pharmacology and Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA.
16
Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
17
Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
18
Department of Pathology and Laboratory Medicine, and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
19
Clinical Development Neurology, AbbVie, North Chicago, IL, USA.
20
Lundbeck, Deerfield, IL, USA.
21
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
22
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
23
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden.
24
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
25
UK Dementia Research Institute at UCL, London, UK.
26
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. kaj.blennow@neuro.gu.se.
27
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden. kaj.blennow@neuro.gu.se.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; Amyloid; Biomarker; Blood; Cerebrospinal fluid; Tau

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