Promising Results from Alzheimer’s Disease Passive Immunotherapy Support the Development of a Preventive Vaccine

Abstract

The apparently near-term effects of the monoclonal antibody BAN2401 in slowing the progression of prodromal Alzheimer’s disease (AD) has created cautious optimism about the therapeutic use of antibodies that neutralize cytotoxic soluble amyloid-β aggregates, rather than removing plaque. Plaque being protective, as it immobilizes cytotoxic amyloid-β, rather than AD’s causative agent. The presence of natural antibodies against cytotoxic amyloid-β implies the existence of a protective anti-AD immunity. Hence, for vaccines to induce a similar immunoresponse that prevents and/or delays the onset of AD, they must have adjuvants that stimulate a sole anti-inflammatory Th2 immunity, plus immunogens that induce a protective immunoresponse against diverse cytotoxic amyloid-β conformers. Indeed, amyloid-β pleomorphism may explain the lack of long-term protection by monoclonal antibodies that neutralize single conformers, like aducanumab. A situation that would allow new cytotoxic conformers to escape neutralization by previously effective monoclonal antibodies. Stimulation of a vaccine’s effective immunoresponse would require the concurrent delivery of immunogen to dendritic cells and their priming, to induce a polarized Th2 immunity. An immunoresponse that would produce besides neutralizing antibodies against neurotoxic amyloid-β oligomers, anti-inflammatory cytokines; preventing inflammation that aggravates AD. Because of age-linked immune decline, vaccines would be significantly more effective in preventing, rather than treating AD. Considering the amyloid-β’s role in tau’s pathological hyperphosphorylation and their synergism in AD, the development of preventive vaccines against both amyloid-β and tau should be considered. Due to convenience and cost, vaccines may be the only option available to many countries to forestall the impending AD epidemic.