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Basic Science and Pathogenesis.

Dinghao An1, Xinxin Zou2, Yun Xu3

  • 1Peking Union Medical College, Beijing, Beijing, China.

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Summary
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Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) risk varies among Alzheimer's disease monoclonal antibodies. Antibody characteristics, like IgG subtype and Aβ binding site, influence ARIA-H incidence, guiding future drug development.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Immunology

Background:

  • Amyloid-related Imaging Abnormalities (ARIA) are adverse effects of amyloid beta monoclonal antibody treatment for Alzheimer's disease.
  • ARIA includes edema-type ARIA and hemorrhage-type ARIA (ARIA-H).
  • Limited comparative analyses exist for ARIA-H incidence across different monoclonal antibodies (mAbs).

Purpose of the Study:

  • To comprehensively compare ARIA-H incidence among seven amyloid beta-targeting mAbs.
  • To investigate the association between specific mAb characteristics and ARIA-H occurrence.
  • To inform future development of Alzheimer's disease therapeutics.

Main Methods:

  • Systematic reviews and meta-analyses of Phase III clinical trials for seven mAbs (Aducanumab, Bapineuzumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab).
  • Evaluation of mAb binding form, affinity, epitope, Fc subtype, and Aβ clearance rate.
  • Differential analysis of ARIA-H occurrence rates standardized across mAbs.

Main Results:

  • The risk of ARIA-H, from highest to lowest, is: Donanemab, Aducanumab, Bapineuzumab, Lecanemab, Gantenerumab, Crenezumab, Solanezumab.
  • ARIA-H risk is associated with mAb characteristics: mature Aβ clearance, lower Aβ oligomer clearance, N-terminus binding, IgG4 subtype, and faster Aβ clearance thresholds increase risk.
  • Monoclonal antibodies with IgG4 structure showed higher ARIA-H likelihood than IgG1.

Conclusions:

  • This study provides a comparative analysis of ARIA-H incidence across seven mAbs.
  • Findings highlight the link between mAb characteristics and ARIA-H, offering insights for drug design.
  • This research can guide the development of safer and more effective Alzheimer's disease treatments.