Targeting β-Amyloid Pathology in Alzheimer's Disease with Aβ Immunotherapy

More than 10 clinical trials of Aβ immunotherapy are currently underway in patients with Alzheimer's disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain β-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid β-peptide (Aβ). Initial experimental and neuro-pathological evidence for clearance of brain β-amyloid in response to Aβ immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of Aβ immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted cross-reactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with pre-existing vascular amyloid pathology, possible relocalization of Aβ from β-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of Aβ antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of Aβ to be therapeutically targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble Aβ into toxic oligomeric aggregation intermediates in the dynamic equilibrium of β-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for Aβ immunotherapy to be one of the first disease-modifying therapies of Alzheimer's disease to be introduced into clinical practice.