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From the Journals

Gantenerumab Linked to ARIA Risk in Early Alzheimer's Disease

86% of ARIA-E cases occurred within the first 64 weeks of gantenerumab treatment, with APOE ε4 homozygotes showing nearly 5-fold increased risk.

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Two phase III trials, GRADUATE I and II, assessed the effects of gantenerumab in early symptomatic Alzheimer's disease with a focus on amyloid-related imaging abnormalities-edema.

The trials, published in JAMA Neurology, spanned 288 sites in 30 countries and involved 1,939 participants, including 993 receiving gantenerumab and 946 placebo.

Amyloid-related imaging abnormalities-edema (ARIA-E) occurred in 24.9% of the gantenerumab recipients vs 2.6% of the placebo recipients. Risk factors included apolipoprotein E (APOE) ε4 homozygosity (hazard ratio [HR] = 4.65), heterozygosity (HR = 2.0), lower cerebrospinal fluid (CSF) Aβ42 (HR = 0.4), and higher Fazekas scores (HR = 1.6). Concurrent ARIA-hemosiderin (ARIA-H) occurred in 43.8% of asymptomatic ARIA-E cases and 64.3% of symptomatic cases. Time to first ARIA-E episode was shorter in APOE ε4 homozygotes (mean = 45.1 weeks) compared with heterozygotes and noncarriers.

Symptomatic ARIA-E, characterized by headaches, confusion, or aphasia, was observed in 1% of participants. Serious cases (e.g., seizures, status epilepticus) occurred in 1.1%, all of whom were hospitalized but recovered without death. Radiological severity, measured using the Barkhof Grand Total Score (BGTS), averaged 21.3 in serious cases compared with 9.0 in asymptomatic cases.

ARIA-E recurred in 46.2% of the participants without baseline cerebrovascular pathology vs 71.4% in those with microhemorrhages or siderosis. Median resolution time for ARIA-E episodes was 8.6 weeks, with homozygous APOE ε4 carriers showing longer times to resolution.

Despite ARIA-E’s incidence, group-level analyses found no significant impact on cognitive (CDR-SB, ADAS-Cog13) or functional (ADCS-ADL) measures at week 116. Adjusted mean differences in CDR-SB were –0.3, favoring gantenerumab, with no evidence of long-term detriment from ARIA-E.

The study highlighted the need for individualized MRI monitoring, especially for APOE ε4 carriers. While gantenerumab did not demonstrate clinical efficacy in slowing Alzheimer's disease progression, the findings enhanced the understanding of ARIA as a class effect of antiamyloid monoclonal antibodies.

Conflict of interest disclosures and supplemental data are available in the original publication.