Distinct serum anti-Aβ antibody patterns in hemorrhagic and inflammatory cerebral amyloid angiopathy manifestations

Objective To study blood anti-Aβ antibodies in the context of spontaneous inflammatory or hemorrhagic CAA manifestations, which are similar to complications occurring after monoclonal anti-Aβ antibody immunotherapies. Methods In this case-control study, serum anti-Aβ antibody isotype, concentration, avidity, and reactivity toward soluble or fibrillary Aβ1-40 and Aβ1-42 isoforms were assessed using an ELISA-based multiplex analysis. Anti-Aβ serologic patterns were defined in CAA and CAA subgroups using multivariable logistic regression analyses. Results Fourty-one healthy aged controls and 64 CAA patients were recruited: 46 with hemorrhagic features (CAA-he) and 18 with CAA-related inflammation (CAA-ri). As compared to controls, the most striking features of CAA-related serological profiles were the following: i) both CAA-he and CAA-ri patients displayed lower binding diversity of anti-soluble Aβ1-40 IgM; ii) CAA-he patients displayed higher anti-soluble Aβ1-40 / fibrillary Aβ1-42 IgG4 concentrations ratio and higher anti-soluble Aβ1-42 IgG4 and IgA avidity; iii) CAA-ri patients displayed higher binding diversity of anti-soluble Aβ1-40 IgG3 and higher anti-fibrillary/soluble Aβ1-42 IgG4 dilution curve steepness ratio. Conclusion This proof-of-concept study revealed anti-Aβ antibody variations in CAA patients, some of which were associated to CAA clinical phenotypes, unveiling pathophysiological insights regarding CAA-hemorrhagic and inflammatory related events. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Study funding supported by the SATT Lutech ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethics committee Paris Ile de France V. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available upon reasonable request.