Passive immunotherapy for Alzheimer's disease: challenges & future directions

Passive immunotherapy with specific antibodies targeting Amyloid beta (A beta) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting A beta peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-A beta antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-A beta antibodies, such as lecanemab (a humanized mAb binds to soluble A beta protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of A beta peptides) and aducanumab (a human mAb binds to the aggregated form of A beta), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-A beta antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-A beta antibodies and other pharmaceutical agents should also be explored.