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Introduction: Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer’s disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency. Methods: Dynamic and statistical analyses of data from 112 individuals that experienced ARIA-E in the open-label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer’s disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer’s disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA-E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA-E. Results: The modeled individual-level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA-E magnitude. ARIA-E dynamics were shown to depend on the interplay between drug-mediated amyloid removal and intrinsic vascular repair processes. Discussion: Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA-E history.

At the 8th International Conference on Clinical Trials in Alzheimer's Disease held November 5-7, 2015 in Barcelona, Spain, promising data were presented on two candidate Alzheimer's disease immunotherapeutic agents, gantenerumab and aducanumab. Trial results demonstrated that the implementation of cerebrospinal fluid and Aβ-PET biomarkers improves trial enrichment and outcome, which has led to a change in targeting strategy as clinical trials would be conducted with earlier, even presymptomatic, stages of the disease. Promising findings of outcomes, as measured by Aβ-PET and cerebrospinal fluid tau and P-tau, were, nevertheless, associated with antibody dose-dependent increased risk of severe adverse effects, specifically amyloid-related imaging abnormalities (ARIA). Aducanumab was associated with concomitant time-, dose-, and APOE-related incidence of ARIA in more than one-half of the patients within the high-dose arm. The future challenge will thus be to find biomarkers more favorably balanced between effective dosing of antibody to remove Aβ versus dosing to limit deleterious side effects. Interest was shown by Roche and Biogen, which promoted high-dose phase 3 trials. However, this generated some concerns related to a reasonable expected further increase in the incidence of severe side effects. What has been learned is challenging primary industry strategies for following-up and monitoring safety and effectiveness of anti-Aβ antibodies in clinical trials. Here, we debate the issue of what is an acceptable balance of treatment side effects, i.e., therapeutic-induced ARIA, versus the positive prospects. Indeed, implementation of biomarkers for ARIA might increase value and reduce waste in the design of immunotherapy trials of Alzheimer's disease.

Background Cerebral amyloid angiopathy-related inflammation (CAA-ri) represents the most readily responsive form of CAA, if diagnosed and treated early. Although CAA-ri typically presents with a monophasic pattern, recurrences have been occasionally reported. Objectives To describe the evolution of the clinical and neuroradiological features of CAA-ri recurrence. Methods From the 60 CAA-ri cases recruited through the iCAβ International Network, we identified those patients who experienced a CAA-ri recurrence at more than 12 months after the first inflammatory event. Neuroradiological evidence of cerebral inflammation (vasogenic edema) and sulcal superficial siderosis or multiple areas of cortical/subcortical microhemorrhages (MHs) were evaluated based upon fluid-attenuated inversion recovery and T2 *-weighted gradient echo or susceptibility weighted imaging, respectively. In one patient, the deposition of amyloid-β was evaluated using 11C-Pittsburgh Compound B-positron emission tomography (PiB-PET). Results Of the 60 cases, two were identified as having experienced a late CAA-ri recurrence, at two and seven years after the first presentation, respectively. At recurrence, the inflammatory lesions colocalized with the appearance of new MHs and were observed in brain areas different from those where the first onset occurred. PiB-PET four months after remission showed particularly low amyloid-β deposition in the left frontal lobe, while no change was observed in the area of the inflammatory relapse. Conclusions Our observations highlight the importance of not underestimating any new neurological symptoms in patients who have already experienced an episode of CAA-ri. Although the frequency of CAA-ri recurrences is rare, in cases of suspected relapse, a prompt clinical and radiological follow-up should be considered in order to obtain a timely diagnosis and treatment, having a potential strong impact on patients' clinical outcome.

Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Aβ) immunotherapy for Alzheimer's disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Aβ autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-Aβ autoantibody as a promising candidate biomarker for ARIA in clinical trials.

Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-β (Aβ) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-Aβ immunotherapy for the treatment of Alzheimer's disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months follow-up, presenting with ARIA and high levels of cerebrospinal fluid anti-Aβ autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-Aβ immunotherapy and that spontaneously occurring in CAA-ri.