Spontaneous and iatrogenic ARIA: Mechanistic insights from CAA‐related inflammation

ARIA-E/H (amyloid-related imaging abnormalities-Edema/Hemorrhage) is an umbrella term that defines the radiographic appearance of MRI images abnormality during treatments with Aβ-lowering monoclonal antibodies (mAbs) for Alzheimer's disease immunotherapy. Today, it is well-recognized that ARIA-E events can also occur spontaneously in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with raised cerebrospinal fluid (CSF) concentrations of spontaneous auto-antibodies against Aβ (aAbs). In this framework, the last years of research and experience of the iCAB international Network generated an increased consensus that therapy-induced ARIA is the iatrogenic manifestation of CAA-ri. Indeed, the natural history of CAA-ri, the response-to-corticosteroid therapy outcomes, the regional and temporal co-localization of radiographic ARIA-E with microglial activation (both on neuropathology and in vivo with TSPO-PET), the downstream negative effects on Aβ-clearance pathways and the related risks for an ARIA-H subsequent event, all provide remarkable supportive evidence that ARIA-E associated with mAbs therapy is iatrogenic CAA-ri. In this talk, we will present and critically discuss the emerging new data supporting the potential of the assay for anti-Aβ (auto)antibody CSF testing as a companion diagnostic and early biomarker for CAA-ri and ARIA in real-world clinical practice and immunotherapy trials. In this framework, we will also present the recently launched "ARIAisCAAri NET" project; an international, prospective, longitudinal, observational Registry and Biobank of patients with ARIA and CAA-ri from the real-world clinical practice aimed at fostering a precision medicine approach and biomarker research collaborations between the AD and CAA community. Funding: Alzheimer's Association Research Grant: 23AARG-1030214 - UncoveriNg Immune MechanIsms and Biomarkers of ARIA (UNIMIB-ARIA Toolkit) References: Piazza F. et al. Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies. Neurology, 2023 Kelly L. et al. Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy. Alzheimer's and Dementia, 2023 Zedde ML et al. CAA-ri and ARIA: Two Faces of the Same Coin? American Journal of Neuroradiology, 2023.