Amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease: from pathophysiology to individualized risk assessment

Monoclonal antibodies targeting amyloid-β are the first approved disease-modifying treatment for Alzheimer’s disease. While amyloid-targeting therapies mitigate the progression of cognitive decline in early-stage Alzheimer’s disease, they are associated with amyloid-related imaging abnormalities (ARIA), an imaging phenomenon presenting as cerebral edema/effusion and/or hemorrhage. Redistribution of parenchymal amyloid-β to perivascular drainage pathways and direct antibody-amyloid interactions within the cerebral vasculature are considered key players in ARIA pathophysiology by promoting inflammation and vascular disruption, thus mirroring hallmarks of inflammatory cerebral amyloid angiopathy. Although ARIA is commonly regarded as an undesired side effect of amyloid-targeting therapies, its association with amyloid-β clearance from the brain opens up the possibility of an alternative interpretation as a physiological reaction to target engagement of anti-amyloid antibodies. Understanding risk factors that promote the occurrence of ARIA and its transformation from asymptomatic imaging phenomenon to its serious and severe form are of great importance to clinical practice. ARIA risk and severity are influenced by apolipoprotein E4 status, microvascular damage, and cerebral amyloid angiopathy, but may be further modulated by antibody binding preferences and comorbidities such as arterial hypertension and ischemic strokes. Identifying individual risk profiles based on deeper insights into pathophysiological pathways may improve patient safety and lead to personalized treatment concepts in Alzheimer’s disease. In this review, we provide a comprehensive summary of ARIA pathophysiology, highlight important risk factors and discuss their relevance in clinical risk management.