Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise

Abstract

The majority of putative disease-modifying treatments in development for Alzheimer's disease are directed against the amyloid-β (Aβ) peptide. Among the anti-Aβ therapeutic approaches, the most extensively developed is immunotherapy-specifically, passive immunization through administration of exogenous monoclonal antibodies (mAbs). Although testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues for better treatments. This review summarizes the experience to date with anti-Aβ mAbs to enter clinical trials for Alzheimer's disease and examines the evidence for clinical efficacy and the major problems with safety-i.e., amyloid-related imaging abnormalities. As mAbs differ considerably with regard to their epitopes and the conformations of Aβ that they recognize (monomers, oligomers, protofibrils, fibrils), the consequences of targeting different species are also considered. An often-cited explanation for the failure of anti-Aβ mAb trials is that they are set too late in the disease process. New trials are indeed evaluating treatments at prodromal and preclinical stages. We should expect to see additional studies of presymptomatic Alzheimer's disease to join the ongoing prevention trials, for which mAbs continue to serve as the mainstay.

Keywords: Alzheimer’s disease; Amyloid-related imaging abnormalities; Amyloid-β; Amyloid-β oligomers; Immunotherapy; Monoclonal antibodies.

Figure 1

Amyloid plaque reduction with aducanumab. (A) Example amyloid positron emission tomography images at baseline and week 54. Individuals were chosen based on visual impression and standard uptake value ratio (SUVR) change relative to average 1-year response for each treatment group (n = 40, n = 32, n = 30, and n = 32). Axial slice shows anatomical regions in posterior brain putatively related to Alzheimer’s disease pathology. (B) SUVR values at baseline, week 26, and week 54. For the 10 mg/kg group, the SUVR composite mean value was 1.16 after 54 weeks of treatment, a value near the cut-point of 1.10 that defines a positive scan (66). Some participants at end point fell below this cutoff and would no longer have met eligibility requirement for study entry at screening. [Reprinted by permission from Sevigny et al. (50).]