Clearance of Amyloid-Beta in Alzheimer's Disease: Shifting the Action Site from Center to Periphery

Amyloid-beta (A beta) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising A beta-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including A beta vaccination (AN1792), anti-A beta antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to A beta oligomerization from plaques, neuroinflammation related to opsonized A beta phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral A beta clearance would be effective and safe for future A beta-targeting therapies.