Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice
8 affiliations
- 1Brigham and Women's Hospital, Boston, MA, USA. [email protected]
- 2Harvard Medical School, Boston, MA, USA. [email protected]
- 3Anhalt University of Applied Sciences, Köthen, Germany
- 4Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany
- 5Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
- 6RIKEN Center for Brain Science, Wako, Japan
- 7Brigham and Women's Hospital, Boston, MA, USA. [email protected]
- 8Harvard Medical School, Boston, MA, USA. [email protected]
Abstract
Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.
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BibTeX
@article{bathini2026early,
title = {{Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice}},
author = {Praveen Bathini and Stephan Schilling and Jens‐Ulrich Rahfeld and David M. Holtzman and Takaomi C. Saido and Cynthia Ann Lemere},
journal = {Molecular Neurodegeneration},
year = {2026},
month = jun,
doi = {10.1186/s13024-026-00965-x},
url = {https://doi.org/10.1186/s13024-026-00965-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice
AU - Praveen Bathini
AU - Stephan Schilling
AU - Jens‐Ulrich Rahfeld
AU - David M. Holtzman
AU - Takaomi C. Saido
AU - Cynthia Ann Lemere
PY - 2026
DA - 2026/06/26
JO - Molecular Neurodegeneration
DO - 10.1186/s13024-026-00965-x
UR - https://doi.org/10.1186/s13024-026-00965-x
AB - Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.
SN - 1750-1326
ER -