Alternatives to Alzheimer’s Disease monoclonal antibody therapy: Preventive vaccines

What is it about?

That aberrant amyloid-beta exists as multiple conformations or conformers, may explain the limited success of monoclonal antibodies in slowing the progression of incipient Alzheimer’s disease. Formation of new conformers would eventually allow the production of species that can escape blocking by an specific monoclonal antibody, causing progression of the disease. Vaccines by inducing a wide response against different amyloid conformers, would block the pathological activity of newly formed species, stopping the disease progression. A critical requirement for an effective vaccine would be the induction of a sole anti-inflammatory immunity, an objective not achieved by the available vaccine prototypes. Several strategies to achieve these goals are discussed.

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Photo by Art by Lønfeldt on Unsplash

Photo by Art by Lønfeldt on Unsplash

Why is it important?

Failure of amyloid-based drugs has been attributed to amyloid being the wrong target, an opinion that ignores the capacity of this protein to exist in a large variety of aberrant forms. Indeed, formation of these pathogenic amyloid aggregates, regardless of the presence of plaque and/or concentration of monomeric amyloid, explains why monoclonal antibodies and BACE inhibitors have failed. That aberrant amyloid triggers tau pathological hyperphosphorylation, points to aberrant amyloid's crucial role in Alzheimer's. It is important for Alzheimer's drug development to focus on the amyloid aberrant oligomers and not on the normal protein. Moreover, due to the nature of the disease a preventive approach will be much more effective than a therapeutic one.

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