Introduction: Naturally occurring autoantibodies (nAbs) against the pathologic isoform of amyloid beta (Aβ42 ) were found in body fluids and indicate a systemic B cell response that may prevent Alzheimer's disease (AD) onset. N-glycans attached to immunoglobulin G-Fab/Fc fragments are features that influence their mechanism of action. The aim was to study the role of N-glycans in nAbs-Aβ42 .
Methods: nAbs-Aβ42 were isolated from AD patients and age-/sex-matched controls (n = 40) and immunoglobulin preparations. Glycosylated/deglycosylated nAbs-Aβ42 were analyzed for their effect on Aβ42 's aggregation, toxicity, and phagocytosis. Glycan structure was analyzed using matrix assisted laser desorption ionization time of flight mass spectrometry.
Results: Deglycosylation of nAbs-Aβ42 had a major impact on Aβ42 's aggregation/toxicity/phagocytosis. The glycan structure showed considerable differences between AD and controls. We were able to predict disease status with a sensitivity/specificity of 95% (confidence interval [CI]: 76.4-99.7%)/100% (CI: 83.9-100%).
Discussion: N-glycosylation has been identified as a critical attribute maintaining the beneficial effects of autoreactive Aβ antibodies. These data have consequences for the development of monocloncal Aβ antibodies and may open new avenues for diagnostics.
Keywords: Alzheimer's disease; N-glycosylation; amyloid beta; autoantibodies; biomarker; immunoglobulin G; nAbs-Aβ42; naturally occurring autoantibodies.
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.