medwireNews: The severity of amyloid-β neuropathology and comorbid cerebrovascular pathology are key risk factors for developing amyloid-related imaging abnormalities-edema (ARIA-E) in patients with Alzheimer’s disease (AD) following treatment with gantenerumab, a study suggests.
Specific baseline risk factors for ARIA-E included the number of superficial siderosis and a higher Fazekas score, which indicates the amount of white matter lesions measured using magnetic resonance imaging (MRI), ranging from 0 (no lesion) to 3 (extensive lesions), with respective significant odds ratios (ORs) of 1.9 and 1.6.
By contrast, lower cerebrospinal fluid (CSF) levels of amyloid-β 42 protected against the condition, with a significant OR of 0.4.
“Since ARIA represents a class effect of first-generation anti-[amyloid-β] mAbs [monoclonal antibodies], understanding ARIA risk factors and symptomatology may inform future clinical decision-making and MRI monitoring. It is also important for ensuring individuals with AD are informed of anti-[amyloid-β] mAbs risks,” write Stephen Salloway (Brown University, Providence, Rhode Island, USA) and colleagues in JAMA Neurology.
The two global phase 3 gantenerumab studies, GRADUATE I and II, previously found no benefit of the drug on clinical decline in participants with early AD, but the studies “provide a rich resource to further characterize ARIA and its longer-term consequences,” the investigators say.
For the current study, data from 1939 participants in the GRADUATE I/II studies and their open-label extensions were assessed. The patients were aged 50 to 90 years with early symptomatic AD and amyloid-β pathology.
The patients were randomly assigned to receive subcutaneous gantenerumab (n=993) or a placebo (n=946) for up to 116 weeks, and the target dose of 510 mg every 2 weeks was achieved after a 9-month up-titration regimen to mitigate ARIA risk. The subsequent open-label extension allowed a mean total of 125 weeks of gantenerumab treatment.
The participants were a mean of 71.7 years old, and most were women (57.0%), had mild cognitive impairment (54.8%), and were being treated for symptomatic AD (64.0%). Almost half (49.7%) of the participants were heterozygous carriers of apolipoprotein E (apoE) ε4, with 17.0% being homozygous carriers and the remaining patients being noncarriers.
ARIA-E and ARIA-hemosiderin (ARIA-H) were seen in a respective 24.9% and 22.9% of participants in the treatment group, and 43.8% and 64.3% of those with asymptomatic and symptomatic ARIA-E, respectively, experienced concurrent new ARIA-H.
At baseline, 8.1% and 2.5% of participants in the treatment group had one to five microhemorrhages and one to three focal areas of superficial siderosis, respectively.
Salloway et al confirmed that those with apoE ε4 alleles were significantly more likely than noncarriers to show signs of ARIA-E, with respective ORs of 1.98 and 4.65 for heterozygous and homozygous carriers.
The researchers note that in multivariate modeling, the only factors that remained significantly associated with ARIA-E risk were being apoE ε4 heterozygous or homozygous, having a higher Fazakas score at screening, having high blood pressure, and being male.
There were no longer statistical associations with total microhemorrhage and superficial siderosis number, higher amyloid burden on positron emission tomography, having more cardiovascular risk factors, lower hippocampal volume, female sex, and higher CSF phosphorylated tau. Nonetheless, the investigators suggest that these results “should be explored further.”
Participants given gantenerumab in the double-blind period of the trials developed ARIA-E more quickly if they were apoE ε4 homozygous and had baseline microhemorrhages and/or superficial siderosis, with signs appearing by a mean of 45.1, 35.7, and 49.2 weeks, respectively, compared with 69.5 weeks for most other patients.
The most common symptoms of ARIA-E were confusion, headache, and aphasia. Serious symptomatic ARIA-E occurred in 1% of patients receiving gantenerumab and the mean radiological severity of the most severe episode per participant was 9.0, 17.5, and 21.3 for asymptomatic, nonserious symptomatic, and serious symptomatic ARIA-E, respectively, on the Barkhof Grand Total Score (BGTS), which ranges from 0 (none) to 60 (severe).
At the group level, there was no effect of ARIA-E on long-term cognition or functional performance and there were no ARIA-related deaths.
“These findings may be considered in clinical practice when prescribing anti-[amyloid-β] mAbs for early AD and developing individualized safety monitoring plans,” say Salloway et al, adding that “[f]urther evaluation of the identified potential ARIA-E risk factors in the context of other anti-[amyloid-β] mAbs is recommended.”
The investigators acknowledge that racial and ethnic minorities were underrepresented in the study, potentially limiting the generalizability of the findings. They add that the “number of symptomatic and serious symptomatic ARIA-E events is low; therefore, conclusions should be interpreted cautiously.”
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