Lessons from antiamyloid-β immunotherapies in Alzheimer's disease

The amyloid hypothesis, that established amyloid-β (Aβ) peptide as the primary cause of Alzheimer's disease (AD) and related dementia, has driven the development of treatments for neurodegeneration for 30 years. During the last decades, more than 200 clinical trials testing more than 30 anti-Aβ immunotherapies have been assessed as potential treatments for AD. A vaccine against Aβ was the first immunotherapy intended to avoid aggregation of Aβ into fibrils and senile plaques, but it dramatically failed. Several other vaccines have been proposed as potential AD treatments, targeting different domains or structural motifs of Aβ aggregates, but without clear clinical benefits or effectiveness. In contrast, anti-Aβ therapeutic antibodies have focused on recognizing and removing Aβ aggregates (oligomers, fibrils, or plaques) by eliciting immune clearance. In 2021, the first anti-Aβ antibody, aducanumab (branded as Aduhelm), received FDA approval under an accelerated approval process. The effectiveness and the overall processes regarding the approval of Aduhelm have been under major criticism and scrutiny, prompting a vote of no confidence by public and private health providers, limiting the coverage only to patients enrolled in clinical trials and not for the general elderly patients. Additionally, another three therapeutic anti-Aβ antibodies are following the same path for potential FDA approval. Here, we present the current status of anti-Aβ immunotherapies under evaluation in preclinical and clinical trials for the treatment of AD and related dementia, with a discussion of the main findings and critical lessons learned from the observations from Phase III, II, and I clinical trials of anti-Aβ vaccines and antibodies.