To characterize amyloid-related imaging abnormalities (ARIA) and associated risk factors among donanemab-treated participants with Alzheimer’s disease (AD).

Amyloid-targeting therapies (ATTs), including donanemab, are used for AD, a progressive, fatal disease. A safety concern associated with ATTs is ARIA (ARIA-edema/effusions (ARIA-E), ARIA-hemorrhages/hemosiderin deposits (ARIA-H)). ARIA clinical trial data can inform management in real-world practice.

Data included early symptomatic AD participants (TRAILBLAZER-ALZ (NCT03367403); TRAILBLAZER-ALZ 2 and its open-label addendum (NCT04437511); TRAILBLAZER-ALZ 6 (NCT05738486)).  The standard donanemab dosing regimen, as used in TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 (titration period of three 700 mg doses every four weeks (Q4W) followed by 1400 mg Q4W), was compared to three alternative dosing regimens in TRAILBLAZER-ALZ 6. Magnetic resonance imaging (MRI) was performed to identify ARIA utilizing standardized protocols including T2*-weighted gradient-recalled echo (GRE) and susceptibility-weighted imaging (SWI).  Penalized regression and decision tree-based models identified variables associated with ARIA risk. 

In the combined TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 dataset (n=1983), ARIA-E and ARIA-H frequencies in donanemab-treated participants were 24.4% and 31.3%, respectively. ARIA-E events were largely mild to moderate radiographically (90.7%) and mostly asymptomatic (76.3%). Baseline variables associated with increased ARIA-E and ARIA-H risk include APOE ε4 allele number and presence of cortical superficial siderosis. In TRAILBLAZER-ALZ 6 (n=843) the modified titration arm had significantly lowered ARIA-E (13.7% versus 23.7% at 24-weeks) and significantly lower ARIA-E severity while retaining the same cumulative exposure and mean amyloid reduction compared to the standard arm.

In addition to T2*GRE-based MRI, randomized TRAILBLAZER-ALZ 6 participants were evaluated with a more sensitive SWI-based MRI at baseline. Applying T2*GRE-based inclusion criteria to SWI scans in randomized participants (n=840) yielded similar results for trial inclusion (38 participants [4.5%] would not have met criteria).

Donanemab trials have identified factors for managing ARIA risk including identifying higher risk patients prior to treatment and a modified titration dosing regimen.