Passive Alzheimer’s immunotherapy: A promising or uncertain option?

• Published in: Ageing research reviews Vol. 90; p. 101996
• Main Authors: Høilund-Carlsen, Poul F., Revheim, Mona-Elisabeth, Costa, Tommaso, Alavi, Abass, Kepp, Kasper P., Sensi, Stefano L., Perry, George, Robakis, Nikolaos K., Barrio, Jorge R., Vissel, Bryce
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.09.2023
• Subjects: Alzheimer’s disease; Amyloid PET; Amyloid-beta; ARIA; Cerebral volumes; Clinical trial; Immunotherapy; FDA; RCT; AD; Alzheimer’s disease; MRI; APOE ε4; FDG; PiB; OLE; Aβ; fMRI; MCI; Amyloid PET; Immunotherapy; ARIA; CSF; SUVr; Clinical trial; PET; Amyloid-beta; Cerebral volumes
• ISSN: 1568-1637; 1872-9649
• DOI: 10.1016/j.arr.2023.101996

The US Food and Drug Administration (FDA)’s recent accelerated approval of two anti-amyloid antibodies for treatment of Alzheimer's disease (AD), aducanumab and lecanemab, has caused substantial debate. To inform this debate, we reviewed the literature on randomized clinical trials conducted with eight such antibodies focusing on clinical efficacy, cerebral amyloid removal, amyloid-related imaging abnormalities (ARIAs) and cerebral volumes to the extent such measurements have been reported. Two antibodies, donanemab and lecanemab, have demonstrated clinical efficacy, but these results remain uncertain. We further argue that the decreased amyloid PET signal in these trials is unlikely to be a one-to-one reflection of amyloid removal, but rather a reflection of increased therapy-related brain damage, as supported by the increased incidence of ARIAs and reported loss of brain volume. Due to these uncertainties of benefit and risk, we recommend that the FDA pauses existing approvals and approval of new antibodies until results of phase 4 studies with these drugs are available to inform on these risk-benefit uncertainties. We recommend that the FDA prioritize FDG PET and detection of ARIAs and accelerated brain volume loss with MRI in all trial patients, and neuropathological examination of all patients who die in these phase 4 trials. •Significant clinical effects are rare, small and of similar size as with conventional therapy.•Presumed amyloid removal is more likely a decreasing PET signal due to increased tissue damage.•Notion of increased tissue damage consistent with therapy-related ARIAs and loss of brain volume.•Recommended: FDG-PET and MRI (for detection of ARIAs and brain volume loss) in all upcoming trials.