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Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.

Overview

Authors: Praveen Bathini1,2, Stephan Schilling3,4, Jens-Ulrich Rahfeld3,4, David M Holtzman5, Takaomi C Saido6, Cynthia A Lemere1,2
ORCID iDs: Praveen Bathini
  1. Brigham and Women’s Hospital, Boston, MA USA
  2. Harvard Medical School, Boston, MA USA
  3. Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany
  4. Anhalt University of Applied Sciences, Köthen, Germany
  5. Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO USA
  6. RIKEN Center for Brain Science, Wako, Japan
Institutions: Brigham and Women's Hospital (United States); Harvard University (United States); Anhalt University of Applied Sciences (Germany); Fraunhofer Institute for Cell Therapy and Immunology (Germany); Washington University in St. Louis (United States); Hope Center for Neurological Disorders (United States); RIKEN Center for Brain Science (Japan)
Journal: Molecular neurodegeneration, volume 21, issue 1, article 57
Dates: received 4 March 2026; accepted 16 June 2026; published online 26 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13024-026-00965-x · PMID 42363270 · PMCID PMC13579800 · OpenAlex W7166103028
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging
Keywords: Alzheimer's disease, Cerebral amyloid angiopathy, Anti-amyloid immunotherapy, Complement activation, ARIA, Blood-brain barrier
MeSH: Cerebral Amyloid Angiopathy*, Complement Activation*, Inflammation*, Alzheimer Disease, Amyloid beta-Peptides, Animals, Antibodies, Monoclonal, Humanized, Blood-Brain Barrier, Brain, Disease Models, Animal, Humans, Mice, Mice, Transgenic (* major topic)
Topic: Intracerebral and Subarachnoid Hemorrhage Research (Neurology, Medicine), according to OpenAlex
Funding: NINDS NIH HHS (R01 NS136122); NIA NIH HHS (P01 AG078106, RF1 AG058657); Alzheimer’s Association (23AARF-1029815)
Citations: cited by 2 papers (Europe PMC); 102 references in the paper

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.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13024-026-00965-x.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

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Data availability

All data supporting the findings of this study are available within the paper. RNAseq data for brain and endothelial transcriptome and ImageJ analysis scripts are available in the supplementary data.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 6 keywords, 13 MeSH terms, 3 funders, 101 references.

Cite

This paper

Bathini, P., Schilling, S., Rahfeld, J.-U., Holtzman, D. M., Saido, T. C., & Lemere, C. A. (2026). Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice. Molecular neurodegeneration, 21(1), 57. https://doi.org/10.1186/s13024-026-00965-x

BibTeX

@article{bathini2026early,
author = {Bathini, Praveen and Schilling, Stephan and Rahfeld, Jens-Ulrich and Holtzman, David M and Saido, Takaomi C and Lemere, Cynthia A},
title = {{Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice}},
journal = {Molecular neurodegeneration},
year = {2026},
month = jun,
volume = {21},
number = {1},
pages = {57},
publisher = {BMC},
issn = {1750-1326},
doi = {10.1186/s13024-026-00965-x},
url = {https://doi.org/10.1186/s13024-026-00965-x},
pmid = {42363270},
pmcid = {PMC13579800}
}

RIS

TY - JOUR
AU - Bathini, Praveen
AU - Schilling, Stephan
AU - Rahfeld, Jens-Ulrich
AU - Holtzman, David M
AU - Saido, Takaomi C
AU - Lemere, Cynthia A
TI - Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice
T2 - Molecular neurodegeneration
J2 - Mol Neurodegener
PY - 2026
DA - 2026/06/26
VL - 21
IS - 1
SP - 57
SN - 1750-1326
PB - BMC
DO - 10.1186/s13024-026-00965-x
UR - https://doi.org/10.1186/s13024-026-00965-x
LA - en
ER -

CSL-JSON

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