Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects

Immunotherapeutic efforts to slowthe clinical progression of Alzheimer's disease (AD) by lowering brain amyloid-beta (A beta) have included A beta vaccination, intravenous immunoglobulin (IVIG) products, and anti-A beta monoclonal antibodies. Neither A beta vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable A beta; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab's phase III trial revealed that primary and secondary end points had been met. Antibody binding to A beta facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar A beta, and binding of antibody-A beta complexes to blood-brain barrier receptors. Antibody binding to A beta in peripheral blood may also promote cerebral efflux of A beta by a peripheral sink mechanism. According to the amyloid hypothesis, for A beta targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of A beta clearance, findings in AD trials involving A beta vaccination, IVIG, and anti-A beta monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the A beta-clearing ability of monoclonal antibodies.