Monoclonal antibodies against β-amyloid (Aβ) for the treatment of Alzheimer's disease: the Aβ target at a crossroads.

Several second-generation active β-amyloid (Aβ) vaccines and passive Aβ immunotherapies are under clinical investigation with the aim of boosting Aβ clearance from the brain of the Alzheimer's disease (AD) patients. However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. Solanezumab, another humanized anti-Aβ monoclonal antibody, was shown to neutralize soluble Aβ oligomers, which is believed to be the more neurotoxic Aβ species. Phase II studies showed a good safety profile of solanezumab while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. The results of four ongoing large Phase III trials on bapineuzumab and two Phase III trials on solanezumab will tell us if passive anti-Aβ immunization is able to alter the course of this devastating disease, and if Aβ is still a viable target for anti-AD drugs.