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Background <p>Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Amyloid-β (Aβ) accumulation has long guided therapeutic development, though early β- and γ-secretase inhibitors failed to demonstrate clinical benefit.</p> Methods <p>A narrative review was conducted based on a structured search of MEDLINE, Embase, and ClinicalTrials.gov, supplemented by manual screening of key reviews and Phase 3 trial reports on amyloid-targeting therapies.</p> Results <p>Monoclonal antibodies including aducanumab, lecanemab, and donanemab achieve significant amyloid clearance and modest slowing of cognitive decline in Phase 3 trials, validating amyloid reduction as a disease-modifying pathway. However, clinical benefits are limited, amyloid-related imaging abnormalities (ARIA) remain safety concerns, and high costs restrict accessibility. Persistent therapeutic gaps reflect the multifactorial pathology of AD, including tau, neuroinflammation, and vascular dysfunction.</p> Conclusions <p>Amyloid-targeting therapies represent the first validated disease-modifying strategy for AD but are not definitive solutions. Future directions include earlier intervention, combination approaches, improved antibody design, and scalable biomarker implementation to enhance real-world impact.</p>

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The evolving landscape of amyloid-targeting therapies in Alzheimer’s disease: progress and challenges

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • Binbin Zhang,
  • Xiaoyun Yu,
  • Xin Zhang

摘要

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Amyloid-β (Aβ) accumulation has long guided therapeutic development, though early β- and γ-secretase inhibitors failed to demonstrate clinical benefit.

Methods

A narrative review was conducted based on a structured search of MEDLINE, Embase, and ClinicalTrials.gov, supplemented by manual screening of key reviews and Phase 3 trial reports on amyloid-targeting therapies.

Results

Monoclonal antibodies including aducanumab, lecanemab, and donanemab achieve significant amyloid clearance and modest slowing of cognitive decline in Phase 3 trials, validating amyloid reduction as a disease-modifying pathway. However, clinical benefits are limited, amyloid-related imaging abnormalities (ARIA) remain safety concerns, and high costs restrict accessibility. Persistent therapeutic gaps reflect the multifactorial pathology of AD, including tau, neuroinflammation, and vascular dysfunction.

Conclusions

Amyloid-targeting therapies represent the first validated disease-modifying strategy for AD but are not definitive solutions. Future directions include earlier intervention, combination approaches, improved antibody design, and scalable biomarker implementation to enhance real-world impact.