Despite significant investment in drug discovery, Alzheimer's disease (AD) continues to be a significant unmet medical need. The effectiveness of CNS drugs is severely hampered by the blood-brain barrier (BBB), and many potential compounds fall short because of poor ADMET characteristics or insufficient brain exposure. Key research gaps on BBB-crossing compounds for AD are identified in this review: A strong dependence on in vitro or in silico predictors that do not generalize well in vivo; A li