Lessons from a Failed γ-Secretase Alzheimer Trial

gamma-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 gamma-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing gamma-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.