Anti-amyloid Monoclonal Antibodies for Alzheimer’s Disease: A New Hope? (Review)

Abstract

INTRODUCTION. Alzheimer’s disease (AD), which becomes more prevalent with increasing life expectancy, is a leading cause of severe cognitive disorders and dementia. In 2021–2024, the Food and Drug Administration (FDA) approved the first disease-modifying therapies (DMTs) based on anti-amyloid monoclonal antibodies (­anti-Aβ mAbs), including aducanumab (accelerated approval), lecanemab, and donanemab. Ongoing studies are evaluating the efficacy and safety of these anti-Aβ mAbs.AIM. This review aimed to examine the prospects and limitations of anti-amyloid DMTs for AD in the context of the current understanding of AD pathogenesis mechanisms.DISCUSSION. According to current concepts, the pathogenesis of AD is primarily driven by the aggregation of amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau protein in the brain, which is accompanied by neurodegenerative changes. The pathogenesis of AD is still being studied. The mechanism of action of FDA-approved anti-Aβ mAbs for the treatment of AD (aducanumab, lecanemab, and donanemab) involves microglial activation followed by amyloid phagocytosis and degradation. The mAbs differ in their affinity to different ­amyloid species. Clinical trials (average duration: 1.5 years) have demonstrated that all 3 anti-Aβ mAbs reliably and significantly reduce the brain amyloid burden (up to complete amyloid clearance with donanemab) and slow down cognitive decline in patients with early-stage AD. Although reliable, the reduction in cognitive decline rates is of limited clinical significance. The most common adverse event of mAb therapy is amyloid-associated imaging abnormalities (ARIA) observed in 20–30% of patients. This complication is a result of amyloid clearance and typically occurs early in the course of treatment. APOE ε4 allele carriers have a higher incidence of ARIA than non-carriers. Most reported cases of ARIA were asymptomatic and resolved over time.CONCLUSIONS. Anti-Aβ mAbs have shown reliable efficacy in reducing the brain amyloid burden and slowing the progression of cognitive decline in AD. However, the widespread use of anti-Aβ mAbs has been hampered by their limited clinical efficacy, invasiveness of diagnosis, high diagnostic and treatment costs, and additional expenses associated with adverse event monitoring.

Keywords

• alzheimer’s disease
• amyloid plaque aggregation
• disease-modifying therapy
• anti-amyloid monoclonal antibodies
• aducanumab
• lecanemab
• donanemab
• amyloid-associated imaging abnormalities
• drug safety