Volume change with gantenerumab: Impact of amyloid-related imaging abnormalities and amyloid removal.

INTRODUCTION: Amyloid-lowering antibodies are associated with neuroanatomical volume changes. This study aims to disentangle the contributions of amyloid-related imaging abnormalities (ARIA) and amyloid clearance to these changes. METHODS: Data from the GRADUATE I and II trials of gantenerumab in early Alzheimer's disease were analyzed. Participants were grouped as placebo, gantenerumab-treated without ARIA, or gantenerumab-treated with ARIA. RESULTS: Gantenerumab treatment was associated with greater parenchymal volume reduction than placebo, with no difference between ARIA and non-ARIA groups. The ARIA group exhibited greater ventricular enlargement which was offset by reduced external cerebrospinal fluid space expansion. Greater amyloid removal correlated with greater volume reduction, although volume changes also occurred in white matter, where amyloid is minimal. Furthermore, the ARIA group showed a flatter relationship between ventricular expansion and clinical decline. DISCUSSION: ARIA are not associated with long-term parenchymal reduction; rather, they are linked to a fluid shift from the external space to the ventricles. Amyloid removal correlates with parenchymal changes, but white matter changes suggest additional mechanisms beyond local clearance. Neither phenomenon was associated with worse clinical outcomes. TRIAL REGISTRATION NUMBER: NCT03444870 and NCT03443973.