Anti-amyloid monoclonal antibodies (mAbs) such as lecanemab and donanemab have recently entered clinical use for Alzheimer’s disease (AD), with pivotal phase 3 trials demonstrating amyloid clearance and cognitive benefit [1] - [3] . In Japan, lecanemab and donanemab were approved 11 months apart, creating a unique naturalistic scenario in which patients completing lecanemab often transitioned to donanemab, partly motivated by infusion convenience (monthly ~30 minutes for donanemab vs biweekly ~1 hour for lecanemab). Sequential administration of two distinct anti-amyloid mAbs is unprecedented in the literature and may engage complementary clearance mechanisms, as lecanemab preferentially binds soluble protofibrils [1] [4] whereas donanemab targets N-terminal pyroglutamate–modified amyloid-β fibrils [2] [5] .

The longitudinal effects of such sequential therapy on brain structure remain unexplored. Volumetric MRI studies in anti-amyloid mAb trials have reported mixed outcomes—ranging from accelerated whole-brain and ventricular atrophy despite amyloid clearance to minimal hippocampal changes [1] - [3] [6] [7] . These patterns have been attributed in part to “pseudoatrophy,” reflecting resolution of inflammation, periplaque gliosis, and associated water content rather than irreversible neuronal loss [4] [8] .

The voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) is a validated morphometric tool for detecting medial temporal and neocortical grey matter loss [9] - [11] . While extensively used in diagnosis and disease monitoring, its responsiveness to disease-modifying therapy has not been established. We therefore conducted a retrospective pilot study to characterize hippocampal and cortical volumetric trajectories during sequential lecanemab → donanemab therapy, compared with untreated AD controls, using all four VSRAD indices.

This pilot study provides the first description of longitudinal hippocampal and cortical volumetric trajectories during sequential lecanemab followed by donanemab therapy in AD, assessed using a standardized voxel-based morphometric method. No prior report has evaluated MRI structural changes in sequential anti-amyloid mAb treatment, and none has applied VSRAD in this therapeutic context.

The principal finding was that sequential therapy was associated with greater progression in whole-brain grey matter atrophy than in untreated controls, together with a non-significant trend toward greater medial temporal Severity index increase. This pattern mirrors findings from pivotal lecanemab [1] [6] and donanemab [2] [7] trials, as well as the phase 2 donanemab study [3] , in which cortical atrophy acceleration occurred despite amyloid clearance.

One possible mechanism is pseudoatrophy—volume reduction due to plaque removal, resolution of gliosis, and fluid shifts, rather than direct neuronal loss [4] [8] . This effect may reflect resolution of neuroinflammation or clearance of plaque-associated tissue volume, which could manifest as diffuse cortical thinning. Because lecanemab [1] [4] and donanemab [2] [5] target distinct amyloid conformers, their sequential use may confer additive or synergistic clearance, providing a biologically plausible basis for the diffuse volumetric changes observed. Importantly, despite these structural changes, no significant between-group difference was observed in functional decline as measured by CDR-GS. This dissociation underscores that therapy-related volumetric trajectories may not immediately translate into clinical benefit or impairment.

The absence of significant differences in medial temporal–restricted indices aligns with biomarker models of AD [8] in which neocortical amyloid deposition and its clearance precede or exceed hippocampal involvement. Longitudinal studies in untreated AD have suggested that hippocampal atrophy may plateau in later stages [15] , while neocortical loss continues.

VSRAD’s whole-brain atrophy metric may thus be more sensitive to therapy-related pseudoatrophy than its medial temporal Severity index. Prior validations against histopathology [9] and differential diagnosis studies [10] [11] underscore its robustness, but our findings extend its potential utility to monitoring disease-modifying therapy effects.

Nevertheless, both treated and untreated groups exhibited ongoing neurodegeneration over the study interval. This echoes trial data showing that anti-amyloid mAbs slow but do not arrest clinical and structural decline [1] - [3] [6] [7] . Future studies should integrate structural MRI with amyloid and tau biomarkers to clarify the pathological basis and clinical relevance of therapy-related volumetric changes.

Limitations include small sample size, single-center design, lack of biomarker correlation, and short follow-up. These factors preclude definitive conclusions but underscore the feasibility and potential value of sequential therapy research.

As a conclusion, sequential lecanemab → donanemab therapy in Alzheimer’s disease is associated with greater whole-brain grey matter atrophy over an 18-month interval compared with untreated controls, consistent with pseudoatrophy observed in monoclonal antibody trials. This study is the first to apply VSRAD in this context, demonstrating its capacity to detect diffuse cortical changes potentially related to sequential amyloid clearance. Larger, prospective, biomarker-integrated studies are warranted to determine the clinical implications of these volumetric patterns.

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

The Institutional Review Board determined that formal approval was not required for de-identified retrospective analysis of data obtained from routine clinical works. Written informed consent was obtained from the participants for publication of the details of their medical data and any accompanying images.

This study was partly supported by a research grant from the General Incorporated Association of Lifelong Health and Wellness Association, Tokyo, Japan.

We thank all participants for allowing us to share this report. We also acknowledge nurses Kai Nayuki and Akiko Hiraoka for their contributions.

Heii Arai: Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Validation; Writing original draft.

Hideo Yamamoto, Yuki Akiba and Junpei Takayama; Methodology, Data curation, Validation, Investigation.

Satoko Aiba: Data curation; Investigation; Methodology; Validation.

Reiko Arai: Conceptualization; Supervision; Visualization; Writing—review & editing.