Targeting amyloid precursor protein secretases: Alzheimer's disease and beyond.

This review evaluates past and present clinical trials, as well as the current preclinical drug candidates focused on treating Alzheimer's disease (AD), in order to better assess the trends in AD drug discovery in context with specific drug mechanisms. The author begins by presenting a summary of the results of over 160 clinical trials targeted at AD, of which 52% have either failed to meet clinical endpoints or stalled (defined for the purpose of this review as no clinical or publicly mentioned progress for at least 3 years). The author postulates that many of the current clinical approaches fail to sufficiently regulate the amyloid cascade that includes, but is not limited to, the production of soluble β-amyloid precursor protein, β-amyloid and/or amyloid precursor protein intracellular domain and including activation of the tau cascade, ultimately translating to no improvement in cognitive function. To support this argument, the author compares clinical results and peer-reviewed opinions to postulate that appropriately focused multifunctional or dual pathway drugs could make the optimal candidate(s) for further investigations.