Although far from validated, the 'amyloid hypothesis' remains the most compelling contemporary hypothesis to explain the cognitive decline observed in Alzheimer's disease (AD). Late-stage clinical trials with both small molecules and immunotherapeutics are ongoing to investigate the role of amyloid in the pathophysiology of AD. Anti-amyloid mAbs are diverse, both in terms of epitope (with affinity for the N- or C-terminus and/or the middle of the protein sequence) and isotype (eg, IgG1 or IgG2 ). The biological activity for a specific mAb may be idiosyncratic, suggesting that additional factors contribute to the mechanism of action. Most large molecules, including mAbs, can gain access to the central compartment, although the CSF exposures are generally regarded to be approximately 0.5% of the plasma levels. Moreover, anti-amyloid mAbs may have both a peripheral and a central mechanism of action; however, the relative contribution of each mechanism for a specific mAb remains to be determined. Thus, the blood-brain barrier, as a transitional site of action, is likely to have a critical role in both the safety and efficacy of each anti-amyloid mAb therapeutic investigated for the treatment of AD.