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Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions

Nature Reviews Neurology volume 21, pages 490–498 (2025)Cite this article

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Abstract

The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice.

Key points

  • The approval of the first disease-modifying therapies — monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) — marks a pivotal shift in Alzheimer disease (AD) management.

  • The immunotherapies significantly reduce brain Aβ levels and have shown the ability to slow cognitive and clinical decline in large, placebo-controlled trials.

  • AD is now conceptualized as a biological continuum, from a preclinical asymptomatic stage to full-blown dementia.

  • Whereas some experts question the modest clinical improvements of amyloid-lowering mAbs, newer therapies such as lecanemab and donanemab show more promising results in reducing amyloid plaques and slowing cognitive decline, with manageable risks such as amyloid-related imaging abnormalities.

  • Implementing mAbs in routine care requires early and accurate diagnosis, access to advanced diagnostics (for example, PET, cerebrospinal fluid and blood biomarkers), and infrastructure for infusions, MRI monitoring and long-term follow-up, posing logistical challenges.

  • Because Aβ clearance alone slows progression by only ~35%, future strategies must target the disease, as well as other pathologies such as tau, inflammation and vascular issues, earlier. Combination therapies are being explored to address the multifactorial nature of the disease.

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Fig. 1: Mechanism of action of anti-amyloid-β monoclonal antibodies.
Fig. 2: Biological targets of amyloid-lowering monoclonal antibodies.

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Acknowledgements

Funding support includes grant U24AG057437 to P.S.A. and R61AG066543, R33AG066543 and R01AG073979 to M.S.R.

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Authors and Affiliations

  1. Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, USA

    Michael S. Rafii & Paul S. Aisen

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  1. Michael S. Rafii
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  2. Paul S. Aisen
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Michael S. Rafii.

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Competing interests

M.S.R. is employed by the University of Southern California and the Alzheimer’s Therapeutics Research Institute (ATRI) and has received grants or contracts from Eisai and Eli Lilly, which were paid to his institution. He has received consulting fees from AC Immune and Ionis. He has participated on a data safety monitoring board or an advisory board for Alzheon, Alnylam, Biohaven, Embic, Prescient Imaging, Positrigo and Recall Therapeutics. P.S.A. has research grants from the National Institutes of Health, Eli Lilly and Eisai, and consults with Merck, Roche, BMS, Genentech, Abbvie, Biogen, ImmunoBrain Checkpoint, Arrowhead, AltPep and Neurimmune.

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Alzheimer’s Network for Treatment and Diagnostics: www.ALZ-NET.org

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Rafii, M.S., Aisen, P.S. Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions. Nat Rev Neurol 21, 490–498 (2025). https://doi.org/10.1038/s41582-025-01123-5

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