Anti-Aß autoantibodies in cerebral amyloid angiopathy-related inflammation: a human spontaneous model of amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease

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 beta (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: we used a novel ultra-sensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibodies concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau and APOE4 genotype were also investigated. Results: during the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ 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 cerebro-vascular Aβ, directly related to autoantibodies concentration and soluble Aβ. The CSF dosage of anti-Aβ 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-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA