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Clinical Trial
. 2025 Jan 1;82(1):19-29.
doi: 10.1001/jamaneurol.2024.3937.

Amyloid-Related Imaging Abnormalities (ARIA) in Clinical Trials of Gantenerumab in Early Alzheimer Disease

Stephen Salloway  1 , Jakub Wojtowicz  2 , Nicola Voyle  3 , Christopher A Lane  3 , Gregory Klein  2 , Marco Lyons  3 , Simona Rossomanno  2 , Francesca Mazzo  3 , Szofia Bullain  2   4 , Frederik Barkhof  5   6 , Tobias Bittner  2   7 , Andres Schneider  2 , Michael Grundman  8 , Roxana Aldea  2 , Mercè Boada  9   10 , Janice Smith  3 , Rachelle Doody  2   7
Affiliations
Clinical Trial

Amyloid-Related Imaging Abnormalities (ARIA) in Clinical Trials of Gantenerumab in Early Alzheimer Disease

Stephen Salloway et al. JAMA Neurol. .

Erratum in

Abstract

Importance: 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.

Objectives: To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E).

Design, setting, and participants: 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.

Interventions: GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk.

Main outcomes and measures: Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments.

Results: 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.

Conclusions and relevance: 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.

Trial registrations: ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Salloway reported grants and personal fees from Biogen, Lilly, Roche, Eisai, Novartis, and NovoNordisk, and personal fees from Prothena, AbbVie, Acumen, CognitionRX, and Kisbee during the conduct of the study. Mr Wojtowicz reported employment and shareholding from F. Hoffmann-La Roche. Dr Lane reported employment and shareholding from Roche Products during the conduct of the study. Dr Klein reported employment and shareholding from F. Hoffmann-La Roche. Dr Lyons reported employment and shareholding from Roche Products. Ms Rossomanno reported employment and shareholding from F. Hoffmann-La Roche outside the submitted work. Dr Mazzo reported employment and shareholding from F. Hoffmann-La Roche during the conduct of the study. Dr Bullain reported personal fees from F. Hoffmann-La Roche during the conduct of the study and personal fees from Biogen International outside the submitted work. Dr Barkhof reported personal fees from Biogen, Prothena, Eisai, Roche, IXICO, Combinostics, and Merck, and grants from Roche and Biogen outside the submitted work. Dr Bittner reported full-time employment and shareholding from F. Hoffmann-LaRoche. Dr Schneider reported employment and shareholding from F. Hoffmann La Roche outside the submitted work. Dr Grundman reported personal fees from Global R&D Partners. Dr Aldea reported a US patent issued for 18/140,583 and employment and stock/stock options from F. Hoffmann-La Roche. Dr Boada reported personal fees from Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, Zambon, and Novo-Nordisk; holding advisory board memberships with Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo-Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma; and lecture fees from Roche, Biogen, Grifols, Nutricia, Araclon Biotech, Servier, and Novo-Nordisk outside the submitted work. Dr Smith reported employment and share options from Roche Products outside the submitted work. Dr Doody reported employment from F. Hoffman-LaRoche during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. GRADUATE I and II: Study Drug Dosing Regimen and Routine Magnetic Resonance Imaging (MRI) Schedule
OLE indicates open-label extension; PET, positron emission tomography; Q2W, every 2 weeks; SC, subcutaneous.
Figure 2.
Figure 2.. Risk Factors for Amyloid-Related Imaging Abnormalities-Edema: Univariate Analyses for Baseline Variables
All the variables are measured at baseline unless indicated otherwise. Univariate analyses for baseline variables with an unadjusted P value of less than .05. Apolipoprotein E (APOE) ε4, dyslipidemia, sex, diabetes, and presence of amyloid-related imaging abnormalities-hemosiderin are treated as categorical variables with associated reference levels of APOE ε4 noncarrier, no dyslipidemia, female, no diabetes, and absent. Aβ indicates amyloid-beta; CSF, cerebrospinal fluid; HR, hazard ratio; LT, log 2 transformed; MRI, magnetic resonance imaging; OR, odds ratio; PET, positron emission tomography; SS, superficial siderosis.
Figure 3.
Figure 3.. Multivariate Modeling With Stepwise Logistic Regression for Baseline Variables
Apolipoprotein E (APOE) ε4 and sex are treated as categorical variables with APOE ε4 noncarrier and female as the reference levels. In addition to those meeting criteria for univariate significance, hippocampal volume, whole-brain volume, systolic blood pressure, and sex were retained in multivariate models of amyloid-related imaging abnormalities-edema risk. In models containing cerebrospinal fluid (CSF) measures, CSF pTau, CSF tTau, and weight were also retained; whereas in amyloid positron emission tomography (PET) models, amyloid PET centiloid, and total number of amyloid-related imaging abnormalities-hemosiderin remained in multivariate models. OR indicates odds ratio. aPer 1 mm Hg; per 10 mm Hg, the OR would be 1.1.
See this image and copyright information in PMC

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