Current Themes and Controversies in the Alzheimer’s Disease Field: Looking Ahead to the CTAD Meeting in San Francisco, November 29–December 2 2022

During the 23 years since Dale Schenk demonstrated that injection of amyloid beta into mice generated antiamyloid antibodies which removed amyloid plaques (1), there have been many efforts to demonstrate the effectiveness of this approach in humans. There have been numerous negative trials, often associated with serious adverse effects, leading many to say that this approach is doomed to failure and that the “amyloid hypothesis” (2) has little merit. The experience with Biogen’s Aducanumab (Aduhelm), a mAb that significantly lowered amyloid plaques in humans (3) was mixed for several reasons. First, they halted their two Phase 3 trials early (apparently because of futility) only then to show that one (but not both) of the trials demonstrated significant slowing of progression. Additionally there were significant side effects, mostly ARIA. Second, the FDA advisory panel strongly recommended not to approve Aducanumab, but the FDA granted accelerated approval based on amyloid plaque removal. Finally, the Center for Medicare Services (CMS) declined to reimburse for Aduhelm, leading to extremely little clinical use. Then, a press release from Eisai last month reported that their single Phase 3 study of Lecanemab, another plaque clearing mAb, met its primary and secondary endpoints, with a significant 27% slowing of the decline in CDR sum of boxes. We have few details of this study, but Eisai is scheduled to present at CTAD and we eagerly await the data. Furthermore, Roche has completed its Phase 3 study of Gantenerumab, and they have informed the CTAD that they also wish to present their results. As of this writing these have not been announced. The Eisai and Roche presentations alone will make this CTAD meeting very informative and exciting. There will be panel discussions of the data, and there will be opportunities for panelists and speakers from the audience to voice their enthusiasm, questions, and concerns about these studies. There are some (including myself) who believe that the cognitive decline associated with plaque clearing mAbs has clinical significance and affirms the amyloid hypothesis, but others disagree and all voices will be heard.