Fc N‐glycosylation of autoreactive Aβ antibodies as a blood‐based biomarker for Alzheimer's disease

Abstract

Abstract INTRODUCTION Naturally occurring autoantibodies (nAbs) against the pathologic isoform of amyloid beta (Aβ 42 ) 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‐Aβ 42 . METHODS nAbs‐Aβ 42 were isolated from AD patients and age‐/sex‐matched controls ( n = 40) and immunoglobulin preparations. Glycosylated/deglycosylated nAbs‐Aβ 42 were analyzed for their effect on Aβ 42 ’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 Aβ 42 ’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.