Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward

Both active and passive anti--amyloid (A) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain A deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of A, were disappointing. Also solanezumab, directed at the mid-region of A, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active A vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-A immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-A immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the A cascade hypothesis of AD.