Characterization of amyloid-related imaging abnormality in the DIAN-TU-001 trial

Background: Amyloid-related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti-beta-amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE-epsilon 4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA-E in the DIAN-TU-001 trial evaluating gantenerumab and solanezumab in DIAD. Method: The DIAN-TU-001 trial enrolled 194 participants, including 144 DIAD mutation-carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB-PET and safety MR, including T2-FLAIR and T2*-GRE. Treatment dosage and APOE-epsilon 4 status were also reported. Result: Eleven participants developed a total of 14 ARIA-E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA-E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA-E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p-value<0.05). ARIA-E participants were PiB-PET+ and 60% were CDR>0. APOE-epsilon 4 tends to be associated with risk for developing ARIA-E (OR=5.0, 95%CI=[1.0,30.4], p-value=0.055). ARIA-E were not observed at initial 225mg dose and were first observed after a titration step (within 4-24 weeks, after 1-6 injections, Table 1). Time-to-resolution of ARIA-E was 10.4 +/- 6.2weeks. Seven of ten ARIA-E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA-E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p-value=0.57). ARIA-E occurred primarily in the occipital lobe (71%) with associated incident ARIA-H (microhemorrhages or superficial siderosis) in 60% of ARIA-E participants. ARIA-E size was associated with microhemorrhage count (Spearman's rho=0.72, p-value<0.05), rate of change (rho=0.78, pvalue<0.01), and baseline PiB-PET (rho=0.68, p-value<0.05). Normalizing by baseline, PiB-PET decreased similarly in ARIA-E+ (-0.21 +/- 0.20) and ARIA-E- (-0.16 +/- 0.20) participants. Conclusion: In DIAD, gantenerumab dose over 225mg increased ARIA-E risk, possibly more for APOE-epsilon 4 carriers. ARIA-E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights formanaging ARIA-E occurrence in future trials.