TY - JOUR
T1 - β-Secretase1 biological markers for Alzheimer’s disease
T2 - state-of-art of validation and qualification
AU - for the Alzheimer’s Precision Medicine Initiative (APMI)
AU - Hampel, Harald
AU - Lista, Simone
AU - Vanmechelen, Eugeen
AU - Zetterberg, Henrik
AU - Giorgi, Filippo Sean
AU - Galgani, Alessandro
AU - Blennow, Kaj
AU - Caraci, Filippo
AU - Das, Brati
AU - Yan, Riqiang
AU - Vergallo, Andrea
AU - Aguilar, Lisi Flores
AU - Akman-Anderson, Leyla
AU - Arenas, Joaquín
AU - Ávila, Jesús
AU - Babiloni, Claudio
AU - Baldacci, Filippo
AU - Batrla, Richard
AU - Benda, Norbert
AU - Black, Keith L.
AU - Bokde, Arun L.W.
AU - Bonuccelli, Ubaldo
AU - Broich, Karl
AU - Cacciola, Francesco
AU - Caruso, Giuseppe
AU - Castrillo, Juan
AU - Cavedo, Enrica
AU - Ceravolo, Roberto
AU - Chiesa, Patrizia A.
AU - Corbo, Massimo
AU - Corvol, Jean Christophe
AU - Cuello, Augusto Claudio
AU - Cummings, Jeffrey L.
AU - Depypere, Herman
AU - Dubois, Bruno
AU - Duggento, Andrea
AU - Emanuele, Enzo
AU - Escott-Price, Valentina
AU - Federoff, Howard
AU - Ferretti, Maria Teresa
AU - Fiandaca, Massimo
AU - Frank, Richard A.
AU - Garaci, Francesco
AU - Geerts, Hugo
AU - Giacobini, Ezio
AU - Giorgi, Filippo S.
AU - Goetzl, Edward J.
AU - Graziani, Manuela
AU - Haberkamp, Marion
AU - O’Bryant, Sid E.
N1 - Funding Information:
HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), and the UK Dementia Research Institute at UCL.
Funding Information:
HH and AV are employees of Eisai Inc. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hj?rnfonden, Sweden (#FO2017-0243), and the Swedish state under the agreement between the Swedish government and the County Councils, and the ALF-agreement (#ALFGBG-715986). Contributors to the Alzheimer Precision Medicine Initiative?Working Group (APMI?WG): Mohammad AFSHAR (France), Lisi Flores AGUILAR (Canada), Leyla AKMAN-ANDERSON (USA), Joaqu?n ARENAS (Spain), Jes?s ?VILA (Spain), Claudio BABILONI (Italy), Filippo BALDACCI (Italy), Richard BATRLA (Switzerland), Norbert BENDA (Germany), Keith L. BLACK (USA), Arun L.W. BOKDE (Ireland), Ubaldo BONUCCELLI (Italy), Karl BROICH (Germany), Francesco CACCIOLA (Italy), Filippo CARACI (Italy), Giuseppe CARUSO (Italy), Juan CASTRILLO? (Spain), Enrica CAVEDO (France), Roberto CERAVOLO (Italy), Patrizia A. CHIESA (France), Massimo CORBO (Italy), Jean-Christophe CORVOL (France), Augusto Claudio CUELLO (Canade), Jeffrey L. CUMMINGS (USA), Herman DEPYPERE (Belgium), Bruno DUBOIS (France), Andrea DUGGENTO (Italy), Enzo EMANUELE (Italy), Valentina ESCOTT-PRICE (Wales), Howard FEDEROFF (USA), Maria Teresa FERRETTI (Switzerland), Massimo FIANDACA (USA), Richard A. FRANK (USA), Francesco GARACI (Italy), Hugo GEERTS (USA), Ezio GIACOBINI (Switzerland), Filippo S. GIORGI (Italy), Edward J. GOETZL (USA), Manuela GRAZIANI (Italy), Marion HABERKAMP (Germany), Marie-Odile HABERT (France), Britta H?NISCH (Germany), Harald HAMPEL (France), Karl HERHOLZ (England), Felix HERNANDEZ (Spain), Bruno P. IMBIMBO (Italy), Dimitrios KAPOGIANNIS (USA), Eric KARRAN (USA), Steven J. KIDDLE (USA), Seung H. KIM (South Korea), Yosef KORONYO (USA), Maya KORONYO-HAMAOUI (USA), Todd LANGEVIN (USA), St?phane LEH?RICY (France), Pablo LEMERCIER (France), Simone LISTA (France), Francisco LLAVERO (Spain), Jean LORENCEAU (France), Alejandro LUC?A (Spain), Dalila MANGO (Italy), Mark MAPSTONE (USA), Christian NERI (France), Robert NISTIC? (Italy), Sid E. O?BRYANT (USA), Giovanni PALERMO (Italy), George PERRY (USA), Craig RITCHIE (Scotland), Simone ROSSI (Italy), Amira SAIDI (Italy), Emiliano SANTARNECCHI (USA), Lon S. SCHNEIDER (USA), Olaf SPORNS (USA), Nicola TOSCHI (Italy), Pedro L. VALENZUELA (Spain), Bruno VELLAS (France), Steven R. VERDOONER (USA), Andrea VERGALLO (France), Nicolas VILLAIN (USA), Kelly VIRECOULON GIUDICI (France), Mark WATLING (England), Lindsay A. WELIKOVITCH (Canada), Janet WOODCOCK (USA), Erfan YOUNESI (France), Jos? L. ZUGAZA (Spain). Alzheimer Precision Medicine Initiative (APMI) https://www.apmiscience.com/
Funding Information:
KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and the Swedish state under the agreement between the Swedish government and the County Councils, and the ALF-agreement (#ALFGBG-715986).
Funding Information:
HH is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. At Sorbonne University, he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université,” and the “Fondation pour la Recherche sur Alzheimer,” Paris, France. HH serves as Senior Associate Editor for the journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019, he had received lecture fees from Servier, Biogen, and Roche; research grants from Pfizer, Avid, and MSD Avenir (paid to the institution); travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics; and consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation; and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyloid-β pathway
KW - Axonal damage
KW - BACE1
KW - Clinical trials
KW - Context of use
KW - Fluid biomarkers
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85093705756&partnerID=8YFLogxK
U2 - 10.1186/s13195-020-00686-3
DO - 10.1186/s13195-020-00686-3
M3 - Review article
C2 - 33066807
AN - SCOPUS:85093705756
SN - 1758-9193
VL - 12
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 130
ER -