Anti-AB autoantibodies and endothelial damage during amyloid-related imaging abnormalities (ARIA): report from the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's disease Biomarkers Collaborative Network

Objectives. Cerebral Amyloid Angiopathy-related inflammation (CAA-ri) is a rare meningoencephalitis characterized by vasogenic edema and multiple cortical/subcortical microbleeds, shearing several aspects with the recently defined Amyloid-Related Imaging Abnormalities (ARIA) occurring in Alzheimer's disease (AD) passive immunization therapies. Here, we investigated the specific role of autologous anti-Aβ antibodies and Tissue Factor Pathway Inhibitor (TFPI) in order to identify novel biomarkers for ARIA. Methods. By a multicenter case-control study in 100 subjects, using a novel ultra-sensitive technique (patent application pending), we evaluated the anti-Aβ autoantibodies and TFPI, as a marker of cerebrovascular impairment, in the CSF of CAA-ri, CAA, AD, MS and controls. Levels of circulating Aβ40 (cAβ40), cAβ42, tau, P-181 tau and APOE4 genotype were also investigated. Results. We demonstrated a direct involvement of anti-Aβ autoantibodies during the occurrence of ARIA, showing that their concentration is specifically increased during the acute phase of CAA-ri (apCAA-ri) and progressively reduced with clinical and radiological remission. Moreover, a strong correlation with the increased mobilization of cAβ40 and cAβ42 during apCAA-ri was shown, followed by their return to control levels and reduced tau and P-181 tau after remission. A parallel increase of the endothelial impairment marker TFPI was also confirmed both in AD and apCAA-ri, in particular in those patients carrying the APOE4 allele . Conclusions. Our data strongly support the hypothesis that the pathogenesis of CAA-ri is mediated by a selective autoimmune reaction against cerebro-vascular Aβ, directly related to autoantibodies concentration and cAβ overloading. The parallel increase of TFPI during apCAA-ri may finally allows to speculate that ARIA is a temporary but necessary event preceding the downstream beneficial Aß-clearance effects of disease modifying therapies (DMTs), further strengthening the increased susceptibility to vascular damage by the therapeutically-administered antibodies. Given the similarities between spontaneous ARIA which develops in CAA-ri and that induced through immunization strategies, CSF anti-Aβ autoantibodies and TFPI may be proposed as useful biomarkers for the diagnosis of CAA-ri, and for a better stratification (at baseline) and the monitoring of ARIA during the upcoming DMTs prevention trials