Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update

The amyloid cascade hypothesis is a useful framework for therapeutic development in Alzheimer's disease (AD). Amyloid b_1-42 (Aβ) has been the main target of experimental therapies, based on evidence of the neurotoxic effects of Aβ, and of the potential adverse effects of brain Aβ burden detected in humans in vivo by positron emission tomography (PET). Progress on passive anti-amyloid immunotherapy research includes identification of antibodies that facilitate microglial activation, catalytical disaggregation, and increased flow of Aβ from cerebrospinal fluid (CSF) to plasma, thus decreasing the neurotoxic effects of Aβ. Recently completed phase 2 and 3 trials of 3rd generation anti-amyloid immunotherapies are supportive of their clinical efficacy in reducing brain Aβ burden and preventing cognitive decline. Data from recent trials implicate these agents as the first effective disease-modifying therapies against AD and has led to the US Food and Drug Administration (FDA) recent approval of aducanumab and lecanemab, under an accelerated approval pathway. The clinical effects of these agents are modest, however, and associated with amyloid-related imaging abnormalities (ARIA). Testing the effects of anti-Aβ immunotherapies in pre-symptomatic populations and identification of more potent and safer agents is the scope of ongoing and future research. Innovations in clinical trial design will be the key for the efficient and equitable development of novel anti-Aβ immunotherapies. The progress in the field of AD therapeutics will bring new clinical, logistical, and ethical challenges, which pose to revolutionize the practice of neurology, dementia care, and preventive cognitive healthcare.