Is passive immunization for Alzheimer's disease 'alive and well' or 'dead and buried'?

Abstract

Background: Passive immunization strategies are under investigation as potential disease-modifying therapies for Alzheimer's disease (AD). Current approaches, based on data demonstrating behavioral improvement and reduced pathology in transgenic animal models, have focused exclusively on immune targeting of beta-amyloid.

Objective: To examine immunization strategies for AD.

Methods: A review of relevant publications.

Results/conclusions: Preliminary results from three Phase II trials suggest both the promise and the need to exercise caution with this method of immunotherapy. The strategies used were distinct, using monoclonal N-terminal, central epitope, and polyclonal antibodies to maximize the efficacy and safety of each approach. The tested compounds are moving into Phase III trials for mild to moderate AD. We await the discoveries that from these studies that may yield the first disease-modifying therapy for AD.

Figure 1

Schematic diagram illustrating the a) molecular and macromolecular transitional states of Aβ and b–d) how they may be influenced by specific passive immunization strategies: a) monomeric Aβ (green) may be either degraded or aggregate to form soluble oligomeric Aβ species (yellow). Soluble oligomeric Aβ aggregates further leading to the deposition of insoluble parenchymal Aβ plaques in the brains of persons with Alzheimer’s disease; b) Antibodies recognizing N-terminal epitopes on Aβ bind to soluble monomeric, oligomeric and insoluble deposited Aβ species presumably shifting the equilibrium from plaque formation to degradation or export from the CNS; c) Antibodies recognizing central epitopes on Aβ recognize soluble monomeric Aβ, but as aggregation occurs, the epitope is hidden preventing binding to soluble oligomeric and insoluble deposited Aβ, enhancing the degradation or removal of monomeric Aβ from the CNS and decreasing the formation of both soluble oligomeric and insoluble deposited Aβ; d) Polyclonal antibody preparations bind multiple antigenic targets on all three transitional forms of Aβ, shifting the equilibrium from plaque formation to degradation or export from the CNS.

Figure 2

Possible mechanisms of cerebral edema or vascular hemorrhage as a result of passive immunization strategies against Aβ: a) Schematic representation of an Aβ-laden arteriole in Alzheimer’s disease. Edema and or vascular hemorrhage may be caused by disruption of vascular integrity through b) the removal of deposited Aβ, c) infiltration of antibody as it binds Aβ in the vessel wall, d) an inflammatory reaction mediated by antibody binding to vascular Aβ and subsequent infiltration of inflammatory cells and other mediators of inflammation, or may involve a combination of any of the above postulated mechanisms.

Figure 2

Possible mechanisms of cerebral edema or vascular hemorrhage as a result of passive immunization strategies against Aβ: a) Schematic representation of an Aβ-laden arteriole in Alzheimer’s disease. Edema and or vascular hemorrhage may be caused by disruption of vascular integrity through b) the removal of deposited Aβ, c) infiltration of antibody as it binds Aβ in the vessel wall, d) an inflammatory reaction mediated by antibody binding to vascular Aβ and subsequent infiltration of inflammatory cells and other mediators of inflammation, or may involve a combination of any of the above postulated mechanisms.