Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: Implications for amyloid-modifying therapies

Objective Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid (A) autoantibodies in the acute and remission phases of CAA-ri. Methods We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-A autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble A40, A42, tau, P-181 tau, and APOE genotype were also investigated. Results During the acute phase of CAA-ri, anti-A autoantibodies were specifically increased and directly correlated with A mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble A and axonal degeneration markers decreased in parallel. Interpretation Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular A, directly related to autoantibody concentration and soluble A. The CSF dosage of anti-A autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-A autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA. Ann Neurol 2013;73:449-458