The amyloid hypothesis has long been the central dogma in drug discovery for 
Alzheimer's disease (AD), leading to many small-molecule and biological drug 
candidates. One major target has been the β-site 
amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma 
companies expending great resources in the search for BACE-1 inhibitors. The 
lack of efficacy of verubecestat in mild-to-moderate AD raises important 
questions about the timing of intervention with BACE-1 inhibitors, and 
anti-amyloid therapies in general, in AD treatment. It also suggests new 
possibilities for discovering BACE-1-targeted compounds with more complex 
mechanisms of actions and improved efficacy. Herein, we review the major 
advances in BACE-1 drug discovery, from single-target small molecule inhibitors 
to multitarget compounds. We discuss these compounds as innovative tools for 
better understanding the complexity of AD and for identifying efficacious drug 
candidates to treat this devastating disease.