title: Lessons from a failed γ-secretase Alzheimer trial.
abstract: γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill.
authors.affiliation: VIB Center for the Biology of Disease, Leuven 3000, Belgium; KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative disorders (LIND), University of Leuven 3000, Belgium; UCL Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK. Electronic address: bart.destrooper@cme.vib-kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001381:Azepines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002986:Clinical Trials as Topic; D003071:Cognition / Q000187:drug effects; D006801:Humans
chemical_list: D016229:Amyloid beta-Peptides; D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine