β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification
Abstract β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s dis...
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doaj-2f3f392684524f368957f3a3ee6b4fe22020-11-25T03:54:05ZengBMCAlzheimer’s Research & Therapy1758-91932020-10-0112111410.1186/s13195-020-00686-3β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualificationHarald Hampel0Simone Lista1Eugeen Vanmechelen2Henrik Zetterberg3Filippo Sean Giorgi4Alessandro Galgani5Kaj Blennow6Filippo Caraci7Brati Das8Riqiang Yan9Andrea Vergallo10for the Alzheimer’s Precision Medicine Initiative (APMI)Sorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière HospitalSorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière HospitalADx NeuroSciences NVDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of GothenburgHuman Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of PisaDepartment of Clinical and Experimental Medicine, University of PisaClinical Neurochemistry Laboratory, Sahlgrenska University HospitalDepartment of Drug Sciences, University of CataniaDepartment of Neuroscience, University of Connecticut HealthDepartment of Neuroscience, University of Connecticut HealthSorbonne University, GRC no 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière HospitalAbstract β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.http://link.springer.com/article/10.1186/s13195-020-00686-3Alzheimer’s diseaseAmyloid-β pathwayAxonal damageBACE1Clinical trialsContext of use |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Harald Hampel Simone Lista Eugeen Vanmechelen Henrik Zetterberg Filippo Sean Giorgi Alessandro Galgani Kaj Blennow Filippo Caraci Brati Das Riqiang Yan Andrea Vergallo for the Alzheimer’s Precision Medicine Initiative (APMI) |
spellingShingle |
Harald Hampel Simone Lista Eugeen Vanmechelen Henrik Zetterberg Filippo Sean Giorgi Alessandro Galgani Kaj Blennow Filippo Caraci Brati Das Riqiang Yan Andrea Vergallo for the Alzheimer’s Precision Medicine Initiative (APMI) β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification Alzheimer’s Research & Therapy Alzheimer’s disease Amyloid-β pathway Axonal damage BACE1 Clinical trials Context of use |
author_facet |
Harald Hampel Simone Lista Eugeen Vanmechelen Henrik Zetterberg Filippo Sean Giorgi Alessandro Galgani Kaj Blennow Filippo Caraci Brati Das Riqiang Yan Andrea Vergallo for the Alzheimer’s Precision Medicine Initiative (APMI) |
author_sort |
Harald Hampel |
title |
β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification |
title_short |
β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification |
title_full |
β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification |
title_fullStr |
β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification |
title_full_unstemmed |
β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification |
title_sort |
β-secretase1 biological markers for alzheimer’s disease: state-of-art of validation and qualification |
publisher |
BMC |
series |
Alzheimer’s Research & Therapy |
issn |
1758-9193 |
publishDate |
2020-10-01 |
description |
Abstract β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm. |
topic |
Alzheimer’s disease Amyloid-β pathway Axonal damage BACE1 Clinical trials Context of use |
url |
http://link.springer.com/article/10.1186/s13195-020-00686-3 |
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