Excess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer\'s disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-β monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3-4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer\'s disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-β therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer\'s disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.