A Voxel-Based Morphometric Pilot Study of Longitudinal Hippocampal and Cortical Changes during Sequential Lecanemab to Donanemab Therapy

Introduction: The anti-amyloid monoclonal antibodies lecanemab and donanemab were approved in Japan 11 months apart, creating a unique situation in which patients completing lecanemab often transitioned to donanemab for convenience. Sequential administration of these two agents has not been previously reported to evaluate longitudinal structural brain changes by using the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). Methods: In this retrospective, single-center pilot study, a total of 21 subjects with Alzheimer’s disease were included: sequential therapy group (n = 8) and untreated controls (n = 13) matched by age, sex, and disease severity. Participants underwent two 3D T1-weighted magnetic resonance imaging scans separated by a treatment or observation interval. The four VSRAD quantitative indices of medial temporal and cortical atrophy were calculated. Results: Patients receiving sequential therapy showed a significantly greater increase in the proportion of grey matter with detectable atrophy compared with controls (p = 0.020). A numerically greater progression of hippocampal atrophy was observed in the therapy group, though the difference was not statistically significant (p = 0.083). Other measures did not differ between groups. Conclusion: This is the first pilot study to report sequential lecanemab followed by donanemab therapy using a standardized voxel-based morphometric approach for longitudinal monitoring in this context. The findings suggest that sequential therapy may influence region-specific patterns of brain volume loss, warranting confirmation in larger studies integrating molecular biomarkers.