Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis

Evaluation of: Sperling R, Salloway S, Brooks DJ et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 11(3), 241–249 (2012). Amyloid-related imaging abnormalities (ARIAs) have been reported in patients with Alzheimer’s disease treated with bapineuzumab, a monoclonal antibody targeting β-amyloid (Aβ). The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recovery sequences thought to represent ‘vasogenic edema’ and/or sulcal effusion (ARIA-E), as well as signal hypointensities on gradient echo/T2* thought to represent hemosiderin deposits. This study was a retrospective analysis in which two neuroradiologists independently reviewed 2572 fluid attenuation inversion recovery MRI scans from 262 participants in two Phase II studies of bapineuzumab and an open-label extension study. In this analysis, several ARIA-E cases were identified that were initially missed in the reported studies of bapineuzumab (42%). Associated clinical symptoms were observed in only 22% of patients with ARIA-E. Occurrence of ARIA-E increased with bapineuzumab dose and presence of apolipoprotein E (APOE) ε4 alleles. The increased risk of ARIA-E in APOE ε4 carriers and the knowledge that vasogenic edema and microhemorrhages may spontaneously occur in cerebral amyloid angiopathy suggest a potential relationship with vascular Aβ burden. The increased risk of ARIA with a high bapineuzumab dose and the findings from a case with PET amyloid imaging also suggest a possible relationship between ARIA-E with Aβ clearance after passive immunotherapy with monoclonal antibodies.

Aducanumab: Appropriate use recommendations

BackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double‐blind, placebo‐controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early Alzheimer’s disease (EAD). Patients could optionally participate in an open label extension (OLE) study at a dose of 10 mg/kg bi‐weekly (Q2W). Amyloid related imaging abnormalities — edema/effusion (ARIA‐E) was a main adverse event of special interest. Incidence of ARIA‐E was lecanemab dose‐dependent and greater in APOE4 carriers. A previously presented logistic model found steady‐state Cmax was a predictor of ARIA‐E incidence and more likely in APOE4 carriers (Hussein, 2019).MethodsThis work expands upon the previously developed logistic model by exploring the effect of APOE4 genotype (noncarrier, heterozygous carrier, homozygous carrier) on ARIA‐E incidence. Modeling was conducted using NONMEM 7.4.3 with data from Study 201 Core. Model predictions were compared to the observed incidence in the OLE study among patients newly treated with lecanemab (ie, placebo‐treated in the Core study).ResultsInclusion of APOE4 genotype as a covariate in the model with three categories (noncarrier, heterozygous carrier, homozygous carrier) led to a statistically significant decrease in model objective function (p <0.001). A model utilizing only 2 categories (homozygous carrier, others) was not significantly different from the model with 3 categories (p = 0.5297). Model‐predicted ARIA‐E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly‐treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.ConclusionsThe incidence of ARIA‐E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA‐E incidence was found between non‐carriers and heterozygous carriers. Data from the larger CLARITY‐AD study will be needed to confirm these findings.Reference: Hussein, et al., Population Pharmacokinetic (PK) and Exposure‐Response (ER) Analyses for Efficacy and Safety of BAN2401 in Patients with Early Alzheimer’s Disease (AD), International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), 2019.

WHAT IS THIS SUMMARY ABOUT? This is a plain language summary of an article published in the journal Brain. People with Alzheimer's disease may receive treatments that target amyloid-β – a protein in the brain that is one of the key characteristics of Alzheimer's disease when it is present in higher levels than normal. This article is about amyloid-related imaging abnormalities (ARIA), which can be adverse events for people with Alzheimer's disease receiving antibody treatments targeting amyloid-β (known as anti–amyloid-β antibody treatments). This article also discusses ways to identify and manage ARIA. ARIA are adverse events that happen due to amyloid-β buildup in the brain or following treatments targeting amyloid-β. ARIA are identified on MRI scans as swelling or bleeding in the brain, and people with ARIA do not typically have symptoms. In rare cases, ARIA can cause serious symptoms or lead to disability. WHAT ARE THE KEY TAKEAWAYS? There are two types of ARIA: ARIA-E (swelling in the brain) and ARIA-H (bleeding in the brain). Presence of an APOE ε4 gene variant and exposure to anti–amyloid-β antibody treatments are major risk factors for ARIA. With the recent availability in the clinic of antibody treatments targeting amyloid-β, increased awareness is needed to identify, monitor and manage ARIA effectively. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS? Uniform detection, monitoring and management of ARIA are essential in patients receiving antibody treatments targeting amyloid-β. To increase ARIA detection in clinical trials and clinical practice, the authors recommend the implementation of uniform imaging protocols and rigorous reporting standards.

After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance. To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment. In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine. Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs. Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.

SPONTANEOUS ARIA WITH EDEMA AND MICROHEMORRHAGES IN A COGNITIVELY NORMAL SUBJECT FROM ADNI

ObjectiveTo evaluate the incidence and characteristics of amyloid‐related imaging abnormalities (ARIA) in patients receiving lecanemab for Alzheimer's disease (AD) in routine clinical practice.BackgroundARIA, presenting as brain edema or hemorrhage (ARIA‐E or ARIA‐H), are significant, potentially severe side effects of anti‐amyloid therapies such as lecanemab and pose major safety concerns for patients and clinicians. Therefore, in order for patients and clinicians to make informed decisions about the risks and benefits of lecanemab, an accurate safety profile based on both robust clinical trial and real‐world data must be developed. While the CLARITY‐AD trial demonstrated the overall safety of lecanemab in a clinical trial setting, real‐world safety data of lecanemab remain limited.MethodsWe conducted a retrospective chart review of 146 patients of the Baylor AT&T Memory Center who had initiated treatment with lecanemab for AD between March 1, 2023, and September 30, 2024, and who had completed at least one post‐treatment MRI. Each patient's APOE genotype, presence and evolution of ARIA over time according to MRI impressions, and clinical impressions were assessed and compared to CLARITY‐AD trial data.ResultsOur results closely mirrored those of the CLARITY‐AD trial.1 In chi‐squared analysis of our data, there were no statistically significant differences (p >0.05) in any of the following measures: the percentages of patients who developed ARIA, ARIA‐E, ARIA‐H, concurrent ARIA‐E and ARIA‐H, microhemorrhages, and superficial siderosis as well as the rates of ARIA‐E, ARIA‐H, and symptomatic ARIA‐E by APOE genotype.ConclusionsReal‐world data of ARIA incidence, severity, and APOE genotype associations closely match the data obtained in the CLARITY‐AD trial, providing further evidence to support the overall safety of lecanemab in routine clinical practice as guided by appropriate use recommendations.

BackgroundLecanemab, a monoclonal antibody targeting amyloid‐β protofibrils, has demonstrated efficacy in reducing amyloid plaque burden and slowing cognitive decline in early Alzheimer’s disease (AD). However, treatment is associated with amyloid‐related imaging abnormalities (ARIA), including vasogenic edema (ARIA‐E) and cerebral microhemorrhages or superficial siderosis (ARIA‐H). The cognitive consequences of ARIA remain insufficiently characterized in real‐world settings.MethodThis retrospective cohort study included 92 individuals with mild cognitive impairment or mild AD who received Lecanemab between 2023 and 2025 at a single community memory clinic. All patients had biomarker‐confirmed amyloid pathology via plasma pTau217 or amyloid PET imaging. Clinical data extracted included demographics, vascular risk factors, APOE4 carrier status, antithrombotic use, infusion number, ARIA subtype and severity, and serial MRI findings. Cognitive performance was assessed longitudinally using the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The primary objective was to evaluate associations between ARIA characteristics and cognitive trajectories.ResultThe majority of patients (n = 58, 63%) did not develop ARIA. Among ARIA‐positive patients (n = 34, 37%), isolated ARIA‐H and combined ARIA‐H with ARIA‐E were the most prevalent subtypes. ARIA‐E resolved in 63% of cases on follow‐up imaging, whereas ARIA‐H persisted in 60%. Most ARIA events (71%) were asymptomatic and mild to moderate in severity. There was no significant difference in cognitive outcomes between patients with asymptomatic ARIA and those without ARIA (mean MMSE 28.1 vs. 28.5, p = 0.34). However, patients with symptomatic ARIA demonstrated significantly lower follow‐up MMSE scores compared to both asymptomatic ARIA and ARIA‐negative individuals (mean MMSE 25.0, p = 0.004 and p = 0.02, respectively). A non‐significant trend toward lower cognitive scores was observed in those with higher ARIA‐H burden.ConclusionIn this real‐world cohort, symptomatic ARIA—particularly ARIA‐H—was associated with measurable cognitive decline. While most ARIA cases were asymptomatic and did not impact cognition, these findings highlight the need for routine neuroimaging surveillance and individualized treatment strategies to optimize safety and cognitive outcomes during Lecanemab therapy. This highlights the need for ongoing assessment of ARIA in clinical practice to enhance the safety and efficacy of amyloid‐targeting therapies in early AD.

Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer’s disease trials of anti-amyloid beta (Aβ) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aβ in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/ sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aβ therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital.

Aims: Alzheimer’s disease continues to be a huge health concern around the globe. Although similar recent developments in anti-amyloid therapy are promising, there is concern about some side effects like ARIA. The purpose of this meta-analysis was to systematically review and compare the safety characteristics of three of the most promising anti-amyloid drugs: lecanemab, donanemab and aducanumab, specifically, the frequency of ARIA-E (oedema) and ARIA-H (haemorrhage).Methods: The present systematic review included only high-quality randomized controlled trials, randomized controlled trials with non-parametric data, and meta-analyses. Data was analysed and visualized by using forest plots, funnel plots and bubble plots. The degree of heterogeneity was examined by I2 of statistics.Results: The antibody lecanemab had the lowest ARIA-E rate at 12.6% and the highest infusion reaction rate at 26.4%. Mild ARIA-E was evident in 24.0% of the participants, whereas mild ARIA-H was detected in 19.7% of the subjects.Of the four candidates, aducanumab showed the highest rate in ARIA-E (30.7%) but the lowest rate in infusion reaction (1.2%). The overall ARIA-H rates appeared to be moderate for all drugs (17.3–19.7%).The odds ratios in the forest plot were above 1 for all the outcomes suggesting increased adverse event risk. There was moderate to high heterogeneity in all the studies examined (I2 = 84.7%).Conclusion: In essence, the risks and benefits of each drug are different. The ARIA-E risk associated with lecanemab is lower than with aducanumab; however, infusion reaction rates remain high. There is reason to believe that such an aggressive ARIA-E profile would ultimately restrict the value of aducanumab and lecanemab. However, donanemab does bring a kind of medium between the two. This review emphasizes the importance of individualized interventions in treating Alzheimer’s dementia.Future Directions: More research is thus needed to understand some of the factors that have confounded heterogeneity, and to find ways of managing some of the risks associated with ARIA. The current study indicates the importance of long-term safety data along with head-to-head comparisons regarding clinical decision-making.

Data from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae. To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E). Secondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023. GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk. Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments. The safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases. These results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended. ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

Aducanumab and the “post-amyloid” era of Alzheimer research?

Amyloid related imaging abnormalities (ARIA) are the most significant risk associated with the use of anti-amyloid monoclonal antibodies (MAB) for Alzheimer's disease (AD). Currently, the presence of the APOE ε4 allele is the best predictor for the development of ARIA. However, the degree of baseline memory impairment has not been fully explored as a risk factor for ARIA. Here, we examined MAB outcomes in a memory clinic population and compared patients with AD who developed ARIA to a case-matched group who did not develop ARIA. Participants who developed ARIA had greater numbers of recall intrusions and false positives, both markers for memory consolidation, at baseline than those who did not develop ARIA. We also observed greater baseline hippocampal and supplementary motor cortical atrophy with ARIA. These differences remained when controlling for the APOE ε4 allele and the presence of pretreatment microhemorrhages. Further investigation of memory impairment and associated brain atrophy is warranted to understand ARIA risk and MAB outcomes in AD.

Amyloid-related imaging abnormalities (ARIA) is a term introduced in 2010 to encompass a spectrum of MRI findings observed in patients receiving investigational anti-amyloid beta (Aβ) immunotherapies for Alzheimer disease (AD). The entity can be broadly categorized into ARIA characterized by edema and effusion (ARIA-E) and ARIA characterized by microhemorrhages and superficial siderosis (ARIA-H). ARIA typically occurs early in the treatment course and has a higher incidence in patients who are apolipoprotein E ε4 allele carriers. ARIA-E has an additional dose dependence, with higher incidence in patients receiving higher doses of anti-Aβ immuno-therapies. ARIA is often asymptomatic and self-resolving. The recognition of ARIA has implications for patient selection and monitoring for Aβ immunotherapies, and its development can potentially lead to a pause or discontinuation of therapy. The FDA's first approval of an Aβ-targeting monoclonal antibody for AD treatment in 2021 will lead to such therapy's expanded use beyond the clinical trial setting and to radiologists more commonly encountering ARIA in clinical practice. This review explores the theorized pathophysiologic mechanisms for ARIA, describes the MRI findings and grading schemes for ARIA-E and AREA-H, and summarizes relevant Aβ immunotherapies. Through such knowledge, radiologists can optimally impact the management of patients receiving targeted AD therapies.

Alzheimer's disease (AD) affects over 6 million people over the age of 65. The advent of new anti-amyloid monoclonal antibodies as treatment for early Alzheimer's disease these immunotherapeutics may slow disease progression but also pose significant risks. Amyloid related imaging abnormalities (ARIA) identified on MRI following administration of these new monoclonal antibodies can cause both brain edema (ARIA-E) and hemorrhage (ARIA-H). While most ARIA is asymptomatic, some patients can develop headache, confusion, nausea, dizziness, seizures and in rare cases death. By analyzing lecanemab, aducanumab, gantenerumab, donanemab, and bapineuzumab clinical trials; risk factors for developing ARIA can be identified to mitigate some of the ARIA risk. Risk factors for developing ARIA-E are a positive Apoε4 carrier status and prior multiple cerebral microhemorrhages. Risk factors for ARIA-H are age, antithrombotic use, and history of prior strokes. With lecanemab, ARIA-E and ARIA-H were seen at lower rates 12 and 17%, respectively, compared to aducanumab (ARIA-E 35% and ARIA-H 19%) in treated patients. ARIA risk factors have impacted inclusion and exclusion criteria, determining who can receive lecanemab. In some clinics, almost 90% of Alzheimer's patients are excluded from receiving these new anti-amyloid therapeutics. This review aims to discuss risk factors of ARIA and highlight important areas for further research. With more anti-amyloid monoclonal antibodies approved by the Food and Drug Administration, considering patient risk factors for developing ARIA is important to identify to minimize patient's risk while receiving these new therapies.