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<p>Alzheimer’s disease (AD) is characterized by progressive accumulation of amyloid-β (Aβ) peptides, initiating a pathological cascade from soluble monomers to toxic oligomers, protofibrils, fibrils, and ultimately extracellular amyloid plaques that contribute to synaptic dysfunction and neuronal degeneration. Aβ is generated through sequential cleavage of amyloid precursor protein by β- and γ-secretases, releasing peptides into the brain and cerebrospinal fluid. Therapeutic monoclonal antibodies have been developed to target distinct Aβ species along this aggregation pathway. Agents such as solanezumab and bapineuzumab primarily bind monomeric Aβ, while aducanumab, gantenerumab, crenezumab, and SAR228810 target aggregated forms, and lecanemab preferentially recognizes protofibrils. Donanemab selectively targets deposited amyloid plaques. Recent regulatory approvals of aducanumab, lecanemab, and donanemab demonstrate significant plaque reduction and modest slowing of cognitive decline in early AD, supporting the amyloid hypothesis. However, multiple clinical failures highlight limitations including late-stage intervention, inadequate targeting of neurotoxic oligomers, and safety concerns such as amyloid-related imaging abnormalities. Future therapeutic strategies emphasize early intervention, improved targeting of soluble toxic species, enhanced brain penetration, and biomarker-guided patient selection. Collectively, monoclonal antibodies validate Aβ as a therapeutic target while underscoring the need to optimize timing, specificity, and clinical impact in AD treatment.</p> Graphical Abstract <p></p>

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Therapeutic monoclonal antibodies targeting amyloid beta in Alzheimer disease current evidence clinical outcomes limitations and future directions

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月30日

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  • Seema Sharma,
  • Sampat Singh Tanwar

摘要

Alzheimer’s disease (AD) is characterized by progressive accumulation of amyloid-β (Aβ) peptides, initiating a pathological cascade from soluble monomers to toxic oligomers, protofibrils, fibrils, and ultimately extracellular amyloid plaques that contribute to synaptic dysfunction and neuronal degeneration. Aβ is generated through sequential cleavage of amyloid precursor protein by β- and γ-secretases, releasing peptides into the brain and cerebrospinal fluid. Therapeutic monoclonal antibodies have been developed to target distinct Aβ species along this aggregation pathway. Agents such as solanezumab and bapineuzumab primarily bind monomeric Aβ, while aducanumab, gantenerumab, crenezumab, and SAR228810 target aggregated forms, and lecanemab preferentially recognizes protofibrils. Donanemab selectively targets deposited amyloid plaques. Recent regulatory approvals of aducanumab, lecanemab, and donanemab demonstrate significant plaque reduction and modest slowing of cognitive decline in early AD, supporting the amyloid hypothesis. However, multiple clinical failures highlight limitations including late-stage intervention, inadequate targeting of neurotoxic oligomers, and safety concerns such as amyloid-related imaging abnormalities. Future therapeutic strategies emphasize early intervention, improved targeting of soluble toxic species, enhanced brain penetration, and biomarker-guided patient selection. Collectively, monoclonal antibodies validate Aβ as a therapeutic target while underscoring the need to optimize timing, specificity, and clinical impact in AD treatment.

Graphical Abstract