Data from the GRADUATE I/II phase 3 trials of gantenerumab in early Alzheimer's disease (AD) have provided insights into the risk factors and characteristics of amyloid-related imaging abnormalities-edema (ARIA-E). The analysis, which included 1939 participants, identified that the severity of amyloid-beta (Aβ) neuropathology and comorbid cerebrovascular pathology may be important baseline risk factors for ARIA-E, in addition to the well-established apolipoprotein E (APOE) ε4 status. The study, published in JAMA Neurology, also found that ARIA-E generally did not impact long-term cognitive or functional performance at the group level.
The GRADUATE I/II trials were randomized, double-blind, placebo-controlled studies involving patients with early symptomatic AD and confirmed Aβ pathology. Participants were randomized 1:1 to receive either gantenerumab or placebo for up to 116 weeks, with a 9-month uptitration regimen to mitigate ARIA risk. Safety monitoring included regular brain magnetic resonance imaging (MRI) to detect ARIA-E and ARIA-hemosiderin (ARIA-H).
Risk Factors for ARIA-E
The analysis revealed that lower cerebrospinal fluid (CSF) Aβ42 levels (HR, 0.4; 95% CI, 0.2-0.7), higher Fazekas scores (HR, 1.6; 95% CI, 1.3-2.0), higher total superficial siderosis count (HR, 1.9; 95% CI, 1.3-2.6), and higher total microhemorrhage count (HR, 1.3; 95% CI, 1.0-1.5) were associated with an increased risk of ARIA-E. APOE ε4 heterozygotes had a hazard ratio of 2.0 (95% CI, 1.4-2.8), while APOE ε4 homozygotes had a hazard ratio of 4.7 (95% CI, 3.2-6.7) for ARIA-E.
Incidence and Characteristics of ARIA
Overall, ARIA-E and ARIA-H occurred in 24.9% and 22.9% of participants treated with gantenerumab, respectively. Among those who developed ARIA-E, 86.2% experienced their first episode by week 64. The study also found that the mean time to first ARIA-E was shorter in participants with baseline microhemorrhages and/or superficial siderosis.
Clinical Impact of ARIA-E
Despite the occurrence of ARIA-E, the study found no significant impact on long-term cognitive and functional performance at the group level. This was assessed using the Clinical Dementia Rating–Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale, Cognition Subscale 13 (ADAS-Cog13), Alzheimer’s Disease Cooperative Study Group Activities of Daily Living (ADCS-ADL), and Functional Activities Questionnaire (FAQ).
Implications for Clinical Practice
The findings suggest that clinicians should consider the severity of Aβ neuropathology and comorbid cerebrovascular pathology, in addition to APOE ε4 status, when prescribing anti-Aβ monoclonal antibodies for early AD. The authors recommend developing individualized safety monitoring plans based on these risk factors. Stephen Salloway, MD, of Brown University, a corresponding author of the study, emphasized the importance of these findings for informing clinical decision-making and ensuring that individuals with AD are fully informed of the risks associated with anti-Aβ mAbs.
Future Directions
The researchers recommend further evaluation of these potential ARIA-E risk factors in the context of other anti-Aβ monoclonal antibodies. Roche is currently developing trontinemab, a novel monoclonal antibody with Brainshuttle technology, which aims to enhance brain access and potentially reduce ARIA risk. Preliminary results from an ongoing phase 1b/2a study suggest rapid amyloid lowering with low ARIA incidence.
Jakub Wojtowicz, MPharm, of F. Hoffmann-La Roche, another corresponding author, noted that the study provides valuable data for characterizing ARIA-E and its longer-term consequences. The insights gained from this analysis may help refine treatment strategies and improve patient safety in the use of anti-amyloid therapies for Alzheimer's disease.
