A promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer's disease

A major hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta (Aβ) plaques in the brain. Sequential cleavage of amyloid precursor protein by BACE1 and γ-secretase generates Aβ. Thus, BACE1 is an attractive AD drug target. Although many BACE1 inhibitors have advanced to clinical trials, most have failed. Some failures may be due to treatment occurring at a late stage when Aβ levels have already led to irreversible neurodegeneration; therefore, there has been a shift toward therapeutic intervention during presymptomatic AD. In this issue of EMBO Molecular Medicine, Neumann et al comprehensively introduce the novel BACE1 inhibitor, CNP520. Their rigorous and robust results stem from in vitro studies, animal models, as well as initial human clinical studies that indicate CNP520 is an exquisitely safe therapeutic agent making it particularly attractive for the prevention of AD. As CNP520 is currently in a clinical trial of presymptomatic individuals at risk for AD, it will be among the first of BACE1 inhibitors to test the prevention paradigm for AD.