Risk for ARIA driven by patient genotype, presence of hemorrhage in early Alzheimer’s

Key takeaways:

• Assessing apolipoprotein E genotypes and baseline MRI data are key to identifying higher risk patients.
• ARIA presence was highest in patients treated with donanemab across all included clinical trials.

SAN DIEGO — The risk for amyloid-related imaging abnormalities in early-stage Alzheimer’s disease is primarily driven by the apolipoprotein E e4 genotype, as well as hemorrhaging present at baseline, according to a speaker.

“Amyloid-related imaging abnormalities are MRI imaging abnormalities consistent with edema that are associated with amyloid-targeting therapies,” Alessandro Biffi, MD, associate vice president of Global Medical Affairs Alzheimer’s Disease at Eli Lilly & Co., which sponsored the study, said during his presentation of late-breaking research at the American Academy of Neurology Annual Meeting.

“They are frequently asymptomatic, but when symptoms are present, they include a variety of non-localizing signs like confusion and dizziness.”

Biffi and colleagues sought to delineate risk factors associated with amyloid-related imaging abnormalities (ARIA) in patients with early symptomatic Alzheimer’s and to assess impact of different doses of donanemab (Leqembi, Eisai/Biogen) on ARIA frequency across four clinical trials in the TRAILBLAZER family: the phase 2 and phase 3 placebo-controlled TRAILBLAZER-ALZ and ALZ 2 trials; the open-label phase of TRAILBLAZER-ALZ 2 trial; and the ARIA-focused TRAILBLAZER-ALZ 6, which featured standard and modified dosing cohorts.

Their analysis included 2,464 individuals across the five treatment groups, 1,614 of whom were carriers of the apolipoprotein E (APOE) e4 gene.

According to results, risk factors associated with ARIA-E at baseline included APOE e4 genotype, number of microhemorrhages and cortical superficial siderosis, while key baseline risk factors for ARIA-H were the presence of APOE e4 and cortical superficial siderosis with the highest frequency of both occurring in patients treated with donanemab.

The researchers also reported that total ARIA-E and ARIA-H were highest in patients treated with donanemab in the TRAILBLAZER-ALZ, ALZ 2 and ALZ 6 studies, with modified titration in ALZ 6 recording lower amounts of total ARIA-E and ARIA-H compared with standard dosing.

Data further showed no evidence of positive interaction between antithrombotic medication and APOE e4 genotypes, nor did those medications increase symptomatic ARIA.

“This dedicated analysis of our phase 2 clinical trial data have shown that the APOE genotype and baseline findings of ARIA data, the pre-treatment MRI … can be used to track progress and to start discussions with patients,” Biffi said.