Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.