β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification
Authors: Hampel Harald , Lista Simone , Vanmechelen Eugeen , Zetterberg Henrik , Giorgi Filippo Sean , Galgani Alessandro , Blennow Kaj , Caraci Filippo , Das Brati , Yan Riqiang , Vergallo Andrea ,   for the Alzheimer’s Precision Medicine Initiative (APMI), Afshar Mohammad , Aguilar Lisi Flores , Akman-Anderson Leyla , Arenas Joaquín , Ávila Jesús , Babiloni Claudio , Baldacci Filippo , Batrla Richard , Benda Norbert , Black Keith L. , Bokde Arun L. W. , Bonuccelli Ubaldo , Broich Karl , Cacciola Francesco , Caraci Filippo , Caruso Giuseppe , Castrillo Juan , Cavedo Enrica , Ceravolo Roberto , Chiesa Patrizia A. , Corbo Massimo , Corvol Jean-Christophe , Cuello Augusto Claudio , Cummings Jeffrey L. , Depypere Herman , Dubois Bruno , Duggento Andrea , Emanuele Enzo , Escott-Price Valentina , Federoff Howard , Ferretti Maria Teresa , Fiandaca Massimo , Frank Richard A. , Garaci Francesco , Geerts Hugo , Giacobini Ezio , Giorgi Filippo S. , Goetzl Edward J. , Graziani Manuela , Haberkamp Marion , Habert Marie-Odile , Hänisch Britta , Hampel Harald , Herholz Karl , Hernandez Felix , Imbimbo Bruno P. , Kapogiannis Dimitrios , Karran Eric , Kiddle Steven J. , Kim Seung H. , Koronyo Yosef , Koronyo-Hamaoui Maya , Langevin Todd , Lehéricy Stéphane , Lemercier Pablo , Lista Simone , Llavero Francisco , Lorenceau Jean , Lucía Alejandro , Mango Dalila , Mapstone Mark , Neri Christian , Nisticò Robert , O’Bryant Sid E. , Palermo Giovanni , Perry George , Ritchie Craig , Rossi Simone , Saidi Amira , Santarnecchi Emiliano , Schneider Lon S. , Sporns Olaf , Toschi Nicola , Valenzuela Pedro L. , Vellas Bruno , Verdooner Steven R. , Vergallo Andrea , Villain Nicolas , Virecoulon Giudici Kelly , Watling Mark , Welikovitch Lindsay A. , Woodcock Janet , Younesi Erfan , Zugaza José L. 
Published: October 2020

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.