The amyloid hypothesis has been the dominant framework for Alzheimer's disease 
(AD) research, including the development of anti-AD therapies. However, none of 
the phase III clinical trials conducted to date that targeted amyloid β (Aβ) 
production, aggregation, or clearance demonstrated a statistically significant 
treatment effect in patients with AD. This includes the approach of using 
monoclonal antibodies that recognize various Aβ epitopes and display different 
binding selectivity. While some monoclonal antibodies have failed in phase III 
trials, several are still in development. Aducanumab (BIIB037) is a human 
antibody that selectively targets aggregated forms of Aβ, including soluble 
oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib 
trial (N=196 patients dosed), aducanumab was shown to reduce Aβ plaques and slow 
decline in clinical measures in patients with prodromal or mild AD, with 
acceptable safety and tolerability. The main safety finding was amyloid-related 
imaging abnormalities (ARIA), a side effect associated with removal of Aβ, which 
was dose-dependent and occurred more often in ApoE ε4 carriers than 
non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase 
III trials of aducanumab in early AD, have been designed based on the outcomes 
of PRIME and on lessons from past clinical trials in patients with AD. Those 
study design features include patient selection with confirmed Aβ pathology, 
ensuring sufficient target engagement, and conducting clinical trials in 
patients at earlier symptomatic stages of AD.