Evaluation of the effects of lecanemab treatment on brain atrophy using voxel-based specific regional analysis system for Alzheimer's disease

Abstract

Background

Lecanemab, a monoclonal antibody targeting amyloid-β (Aβ), has been shown to reduce Aβ plaques and slow cognitive decline in patients with Alzheimer's disease (AD). However, its effect on brain structure in real-world clinical settings remains unclear. The voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) enables quantitative assessment of brain atrophy, particularly in the medial temporal lobe, using MRI.

Objective

To evaluate the effects of lecanemab on brain structure by analyzing changes in Z-scores derived from VSRAD in AD patients treated with lecanemab in actual clinical practice.

Methods

This retrospective study included 16 patients with AD who received four biweekly administrations of lecanemab (10 mg/kg) between February 2023 and August 2024. Amyloid pathology was confirmed via ¹⁸F-flutemetamol PET and cerebrospinal fluid Aβ_42/40 ratio. VSRAD analysis was performed using three-dimensional sagittal T1-weighted MRI scans obtained before the first and after the fourth lecanemab administration. Changes in the Z-score of medial temporal lobe (MTL) and MTL/whole brain ratios were assessed.

Results

After four doses of lecanemab, the Z-score of MTL in AD patients significantly decreased from 1.61 ± 0.76 to 1.38 ± 0.67 (p < 0.01), and the MTL/whole brain ratio significantly decreased from 6.47 ± 6.48 to 4.59 ± 4.80 (p < 0.02).

Conclusions

Lecanemab treatment was associated with a significant reduction in the Z-score of MTL, indicating a decrease in brain volume. The clinical significance of this brain volumetric change remains uncertain, and hence longitudinal studies linking brain volume reduction with clinical outcomes, including cognition, are warranted.

Keywords

Alzheimer's disease amyloid-β magnetic resonance imaging therapeutics/treatments

Introduction

The voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) is a cutting-edge imaging tool used to assess and diagnose Alzheimer's disease (AD), by analyzing structural changes in the brain using magnetic resonance imaging (MRI).^1–3 By leveraging voxel-based morphometry, a method that quantifies brain structure by comparing the density of gray matter voxels throughout the brain, VSRAD enables the detailed analysis of subtle changes in brain structure.⁴ A key advantage of VSRAD is its ability to detect early stage brain atrophy, which is crucial for the timely diagnosis and intervention of AD. VSRAD primarily focuses on detecting atrophy in key brain regions, particularly the medial temporal lobe, which is particularly vulnerable to the neurodegenerative processes associated with AD.^1,3 The medial temporal structures, including the entire entorhinal cortex, hippocampus, and amygdala, were designated as the volume of interest (VOI) because they demonstrate substantial atrophy even in patients with very mild AD.⁵ The “severity of VOI atrophy” calculated from the Z-score, which is a central feature of VSRAD, provides a standardized metric for quantifying the degree of brain atrophy in the entire entorhinal cortex, hippocampus, and amygdala.^5–8 This score represents the number of standard deviations a patient's measurement deviates from the mean of a control population. Higher Z-scores generally indicate more severe atrophy, correlating with more advanced disease pathology. For example, a Z-score of +2 indicates that the observed atrophy exceeds the control population's mean by 2 standard deviations, signifying notable neurodegeneration. In this way, because the VSRAD can quantitatively indicate the degree of atrophy in the VOI, it is a useful quantitative measure for tracking AD progression and evaluating therapeutic interventions in both clinical practice and research.

Lecanemab, which was introduced to the Japanese market in December 2023, marked a pivotal advancement in AD treatment, as it targets the underlying pathology of the disease. Most AD treatments available to date have focused on managing symptoms without directly addressing the accumulation of amyloid-β (Aβ), which is a hallmark of AD. After the clarification that Aβ play a crucial role in AD pathogenesis, extensive research on new therapeutic approaches aimed at targeting Aβ have been performed. Lecanemab, a monoclonal antibody that was developed by Eisai and Biogen, is designed to bind to Aβ plaques and their soluble precursors, Aβ protofibrils. By binding to the surface of Aβ protofibrils, lecanemab mitigates their direct cellular toxicity,⁹ and by binding to the Aβ plaques, it removes them. The efficacy of lecanemab in slowing cognitive decline, particularly in patients in the early stages of AD, has been supported by clinical trials. In particular, the Phase 3 Clarity AD trial demonstrated that lecanemab not only removes Aβ, but also slows cognitive decline in AD patients, indicating its potential to modify the course of AD progression.¹⁰

Given that VSRAD provides a robust method for detecting and quantifying early brain atrophy, it presents an invaluable tool for evaluating the structural changes induced by new therapeutic interventions such as lecanemab. Changes in Z-scores during the course of treatment may provide important insights into the effect of lecanemab on brain structure.

In this study, we aimed to evaluate the effects of lecanemab on brain structure, by analyzing changes in quantitative Z-scores using VSRAD in AD patients administered with lecanemab. To the best of our knowledge, this is the first study to investigate the effects of lecanemab on brain structure of AD patients in the real world.

Methods

Participants and confirmation of amyloid pathology

This study included 16 patients who visited the Memory Disorders Clinic of the Department of Geriatrics, Tokyo Medical University, between February 2023 and August 2024. All patients were diagnosed as having probable AD based on the National Institute on Aging and Alzheimer's Association diagnostic criteria of 2011.¹¹

Aβ pathology was confirmed by both amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis in all patients. Amyloid PET was performed using the radiotracer ¹⁸F-flutemetamol, and the Centiloid scale^12,13 was calculated. For CSF analysis, the Aβ_42/40 ratio^14,15 was measured using a commercial service (SRL, Inc., Tokyo, Japan), and used as an indicator of AD diagnosis.

Lecanemab administration

Lecanemab treatment was administered at a dose of 10 mg/kg body weight every two weeks.

MRI acquisition and VSRAD analysis

For VSRAD analysis, three-dimensional sagittal T1-weighted spin-echo images were obtained using the following parameters: field of view, 25.6 cm × 25.6 cm; matrix size, 256 × 256; slice thickness, 1.0 mm; and voxel dimensions, 1.0 mm × 1.0 mm × 1.0 mm. The severity of VOI atrophy was calculated using the VSRAD Advance 2 software (Eisai Co., Tokyo, Japan). The severity of VOI atrophy was determined by calculating the mean Z-score within the target VOI (hippocampus, amygdala, and most of the olfactory cortex, which collectively correspond to the medial temporal lobe [MTL])⁵ and comparing the patient's voxel-wise gray matter concentration with the healthy individual database template.¹⁶ In this study, to avoid potential misunderstanding, “severity of VOI atrophy” was defined as the “Z-score of MTL.”

The Z-score of MTL was assessed by comparing scores obtained before the first lecanemab administration (within approximately 6 months before the initial administration), and scores obtained after the fourth administration (approximately 8 weeks after the initial administration). Additionally, the “VOI/whole brain atrophy ratio” was calculated using the VSRAD Advance 2 software. This value was calculated by dividing the proportion of atrophic regions with a Z-score of 2 or higher within the VOI by the proportion of atrophic regions with a Z-score of 2 or higher in the whole brain.¹⁶ To avoid potential misunderstanding arising from the term “VOI/whole brain atrophy ratio,” it was defined in this study as the “MTL/whole brain ratio.” Comparisons were also made between the value before the first lecanemab administration and that after the fourth lecanemab administration.

Before the first administration of lecanemab, 1.5-tesla (T) MRI was used for 5 patients, and 3T MRI was used for 11 patients. For the scan conducted after the fourth lecanemab administration, 3T MRI was used for all patients.

To investigate the correlation between changes in the Z-score of MTL and amyloid PET results, correlations were evaluated between the Centiloid scale of amyloid PET and the following two indices: (1) the change in Z-score of MTL, defined as before the first administration of lecanemab minus that after the fourth administration, and (2) the ratio of change in Z-score of MTL, defined as after the fourth administration divided by that before the first administration.

Statistical analysis

Statistical analyses of the changes caused by lecanemab administration were performed using the Wilcoxon signed-rank test, and the Spearman's rank correlation coefficient for the correlation between Z-score of MTL and amyloid PET, using IBM SPSS Statistics software version 25 (Chicago, IL, USA). A p-value of less than 0.05 was considered to indicate a statistically significant difference between the two groups.

Ethical approval

This study was approved by the Ethics Committee of Tokyo Medical University (study approval no.: T2025-0018).

Results

Table 1 shows the characteristics of the patients, including sex, age, Mini-Mental State Examination score, Clinical Dementia Rating score, Aβ_42/40 ratio, and the Centiloid scale.

Table 1.

Characteristics of the patients.

n = 16
Sex (men / women)	5 / 11
Age (y) (mean ± SD)	68.8 ± 8.9
MMSE score (mean ± SD)	24.6 ± 1.9
CDR global score (mean ± SD)	0.5 ± 0.0
Aβ_42/40 ratio (mean ± SD)	0.51 ± 0.09
Centiloid scale (mean ± SD)	73.7 ± 21.9

MMSE: Mini-Mental State Examinaton; CDR: Clinical Dementia Rating; Aβ: amyloid-β; SD: standard deviation.

Table 2 shows the current medications, lecanemab dose, and MRI Tesla strength before the first administration of lecanemab for each patient. Medications were not changed in any of the patients during the observation period.

Table 2.

Detailed information of each patient.

Patient no.	Current medications	Lecanemab dose (mg)	MRI tesla strength*
1	Benfotiamine (75 mg/day), donepezil hydrochloride (5 mg/day)	520	3
2	None	430	3
3	Atorvastatin calcium hydrate (5 mg/day), bazedoxifene acetate (20 mg/day), eldecalcitol (0.75 μg/day)	510	3
4	Amlodipine besylate (2.5 mg/day), azilsartan (20 mg/day), donepezil hydrochloride (5 mg/day)	580	3
5	Desloratadine (5 mg/day), rosuvastatin calcium (2.5 mg/day), tocopherol nicotinate (200 mg/day)	490	1.5
6	Donepezil hydrochloride (5 mg/day), rosuvastatin calcium (5 mg/day), sitagliptin phosphate hydrate (50 mg/day)	450	3
7	Eldecalcitol (0.75 μg/day), limaprost alfadex (10 μg/day), mecobalamin (1000 mg/day), sodium risedronate hydrate (2.5 mg/day)	350	3
8	Amlodipine besilate (2.5 mg/day), atenolol (25 mg/day), atorvastatin calcium hydrate (5 mg/day), sulpiride (100 mg/day)	470	1.5
9	None	550	1.5
10	Amlodipine besilate (5 mg/day), candesartan cilexetil (8 mg/day), carvedilol (10 mg/day), donepezil hydrochloride (5 mg/day), mirabegron (50 mg/day)	450	3
11	Amlodipine besilate (5 mg/day), azilsartan (20 mg/day), donepezil hydrochloride (5 mg/day), ursodeoxycholic acid (200 mg/day)	600	3
12	Amlodipine besilate (5 mg/day), irbesartan (50 mg/day), levothyroxine sodium hydrate (50 μg/day), polycarbophil calcium (1500 mg/day), ramosetron hydrochloride (5 μg/day), rosuvastatin calcium (2.5 mg/day)	600	1.5
13	Donepezil hydrochloride (5 mg/day)	490	3
14	Atorvastatin calcium hydrate (10 mg/day), clopidogrel sulfate (75 mg/day), donepezil hydrochloride (5 mg/day), montelukast sodium (10 mg/day), nifedipine (40 mg/day)	630	1.5
15	Amlodipine besilate (2.5 mg/day), bilastine (20 mg/day), donepezil hydrochloride (5 mg/day)	600	3
16	Pitavastatin calcium hydrate (2 mg/day), ibotin (4 mg/day, magnesium oxide (500 mg/day)	420	3

*MRI Tesla strength at the time before the first administration of lecanemab.

Table 3 shows a comparison of the Z-score of MTL and MTL/whole brain ratio before the first and after the fourth administration of lecanemab. The mean Z-score of MTL before the first administration was 1.61 ± 0.76, whereas that after the fourth administration was 1.38 ± 0.66, demonstrating a statistically significant difference (p < 0.05). In terms of the MTL/whole brain ratios, the mean ratio before the first administration was 6.76 ± 6.44, whereas that after the fourth administration was 4.92 ± 4.83, also showing a statistically significant difference (p < 0.05). Box-and-whisker plots illustrating the severity of Z-score of MTL (Figure 1) and MTL/whole-brain ratio (Figure 2) before the first administration and after the fourth administration of lecanemab are shown. Figure 3 shows individual patient changes in the Z-score of MTL before the first administration and after the fourth administration of lecanemab.

Figure 1.

Comparison of the Z-score of MTL before the first and after the fourth administration of lecanemab. The box-and-whisker plot shows a comparison of the Z-score of MTL between before the first (Before) and after the fourth administration of lecanemab (After). The numbers annotated next to the outliers correspond to the patient numbers in Table 2.

Figure 2.

Comparison of the MTL/whole brain ratios before the first and after the fourth administration of lecanemab. The box-and-whisker plot shows a comparison of the MTL/whole brain ratios between before the first (Before) and after the fourth administration of lecanemab (After). The numbers annotated next to the outliers correspond to the patient numbers in Table 2.

Figure 3.

Individual changes in the Z-score of MTL before the first and after the fourth administration of lecanemab. The graph shows the changes in the Z-score of MTL between before the first (Before) and after the fourth (After) administration of lecanemab for each individual patient. The numbers correspond to the patient numbers listed in Table 2.

Table 3.

Comparison of the Z-score of MTL and MTL/whole brain ratio before and after lecanemab administration.

(n = 16)	Before the first administration of lecanemab	After the fourth administration of lecanemab	Z-statistic	p
Z-score of MTL (mean ± SD)	1.61 ± 0.76	1.38 ± 0.67	−3.157	p < 0.01^a
MTL/whole brain ratio (mean ± SD)	6.47 ± 6.48	4.59 ± 4.80	−2.385	p < 0.02^a

a: Wilcoxon signed-rank test.

SD: standard deviation.

Similar trends were observed in the 11 patients who underwent 3 T MRI both before the first administration and after the fourth lecanemab administration (Table 4).

Table 4.

Comparison of the Z-score of MTL and MTL/whole brain ratios before the first and after the fourth lecanemab administration in patients analyzed using 3 T MRI.

(n = 11)	Before the first administration of lecanemab	After the fourth administration of lecanemab	Z-statistic	p
Z-score of MTL (mean ± SD)	1.80 ± 0.79	1.53 ± 0.67	−2.759	p < 0.01^a
MTL/whole brain ratio (mean ± SD)	7.49 ± 7.11	5.08 ± 5.38	−2.312	p = 0.02^a

a: Wilcoxon signed-rank test.

SD: standard deviation.

No evidence of cerebral edema was detected in any of the MRI images obtained after the fourth administration of lecanemab. Figure 4 shows the MRI images obtained before the first and after the fourth administration of lecanemab from the patient that demonstrated the most pronounced reduction in Z-score of MTL. (This image corresponds to the patient No. 2 in Table 2).

Figure 4.

MRI images before the first and after the fourth lecanemab administration in a patient with marked reduction of the Z-score of MTL. FLAIR axial MRI images obtained before the first (left) and after the fourth (right) administration of lecanemab in the patient who demonstrated the most pronounced reduction in the Z-score of MTL, as evaluated using VSRAD.

Table 5 shows the correlation between changes in the Z-score of MTL and amyloid PET results. Neither the change in Z-score of MTL nor the ratio of change in Z-score of MTL showed a significant correlation with the Centiloid scale of amyloid PET (ρ = −0.04, p = 0.89; ρ = −0.24, p = 0.36, respectively).

Table 5.

Correlation between change of the Z-score of VOI and amyloid PET results.

(n = 16)	Mean ± SD	Correlation with the Centiloid scale of amyloid PET
Change in Z-score of MTL	0.23 ± 0.20	ρ = −0.04, p = 0.89^a
Ratio of change in Z-score of MTL	0.85 ± 0.13	ρ = −0.24, p = 0.36^a

a: Spearman's rank correlation coefficient.

SD: standard deviation.

Discussion

Reduction in Z-score of MTL following lecanemab administration

In this study, we observed a significant reduction in the Z-score of MTL following four biweekly administrations of lecanemab in patients with AD. This finding suggests that lecanemab may exert structural effects on the brain within a relatively short period, which is a particularly intriguing observation. This raises the possibility that the volume in the VOI (i.e., indicating the MTL) may have increased, or that the brain volume may have decreased as a result of lecanemab administration.

First, we will discuss the possibility that the volume of the MTL may have increased. As hippocampal neurons have been shown to undergo regeneration,¹⁷ if lecanemab exerts a neuroprotective effect on the hippocampus, it may lead to hippocampal neuron regeneration and an increase in the volume of the MTL. For example, although not a peer-reviewed publication and thus not suitable for citation, in a presentation titled “Clarity AD: A Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group, 18-Month Study Evaluating Lecanemab in Early Alzheimer's Disease” at the Clinical Trials on Alzheimer's Disease conference held in San Francisco, CA, USA (November 29 to December 2, 2022), researchers reported an increase in hippocampal volume following lecanemab administration. However, considering that the turnover rate of neuronal cells in the human hippocampus is very slow,¹⁸ it is unlikely that substantial regeneration capable of significantly increasing hippocampal volume would occur over a short period of approximately eight weeks. Therefore, it is unlikely that the observed reduction in the Z-score of MTL reflects a substantial recovery of the hippocampus owing to a neuroprotective effect of lecanemab. Another potential explanation is that lecanemab, which is known to increase vascular permeability,¹⁹ may have induced edema in the hippocampus, thereby leading to an apparent increase in the volume of the MTL. However, no MRI findings suggestive of edema were observed in any of the acquired images. Furthermore, considering that Aβ deposition—the target of lecanemab—is low in the hippocampus during the early stages of AD,²⁰ the possibility that the increased vascular permeability induced by lecanemab contributed to an increase in MTL volume is considered to be low.

Second, we will discuss the possibility that the observed reduction in the Z-score of MTL may have resulted from the brain volume decrease induced by lecanemab administration. In VSRAD, the Z-score of MTL is calculated by comparing it with a database of healthy individuals. Therefore, if the volume decrease in the cerebral cortex is relatively larger than in the MTL, the image may be stretched, potentially resulting in a relative decrease in the Z-score of MTL. In fact, the MTL/whole brain ratio also significantly decreased, indicating that the rate of whole brain atrophy was greater than the rate of MTL atrophy.

We hence concluded that the observed reduction in the Z-score of the MTL in this study was attributable to brain volume decrease induced by lecanemab administration, with a greater reduction in the cerebral cortex than in the MTL. A reduction in whole-brain and hippocampal volumes following lecanemab administration has also been reported in the phase 2 clinical trial of lecanemab.²¹ However, brain volumetric assessments in that study were conducted only at 6, 12, and 18 months after the start of lecaemab administration. The results of our present study suggest that brain volume reduction may occur at an earlier stage after the initiation of lecanemab treatment.

There are two main possible explanations for the reduction in brain volume observed following lecanemab administration. One possibility is that the decrease is a result of amyloid removal induced by lecanemab, and the other is that lecanemab accelerates neurodegeneration and thereby causes a true reduction in brain tissue volume.

First, we will discuss the possibility that amyloid removal induced by lecanemab may have contributed to the reduction in brain volume. The hypothesis that Aβ removal results in an apparent reduction in brain volume was recently proposed by Belder et al.²² and is referred to as “amyloid-removal-related pseudo-atrophy.” It is known that in the early stages of AD, more Aβ accumulates in the cerebral cortex than in the MTL.^20,23 If we assume that the amount of Aβ deposition correlates with the reduction in brain volume owing to lecanemab administration, it is plausible that lecanemab led to a greater reduction in cortical volume than MTL volume, resulting in a decrease in the Z-score of MTL. In general, it has been reported that the amount of Aβ deposition in patients with AD is relatively limited,²⁴ and even complete removal of Aβ is unlikely to result in a measurable change in brain volume.²⁵ However, Aβ plaques contain not only amyloid-β but also a large number other proteins and dystrophic neurites, and are thought to be associated with reactive glia and fluids. The proportion of cortical grey matter occupied by Aβ plaques in the post-mortem brains of patients with AD has been estimated to be approximately 6% to 8%, which is approximately 2% to 3% of the total brain volume.²² Therefore, it is reasonable to assume that the removal of Aβ and its plaques by lecanemab could lead to a reduction in brain volume. To support this hypothesis, we investigated whether there was an association between the Centiloid scale, which reflects the overall burden of amyloid deposition in the brain,¹³ and the Z-score of MTL. However, no significant association was found between the two. Nevertheless, an increase in total amyloid burden does not necessarily imply a uniform increase in Aβ deposition across both the MTL and the cerebral cortex. In other words, the distribution of amyloid deposition in the brain is heterogeneous; some regions may exhibit substantial deposition while others may show minimal accumulation. Therefore, even if no clear association was observed between the overall amyloid burden, as measured by the Centiloid scale, and the Z-score of MTL, this result does not necessarily contradict our hypothesis. To further substantiate our hypothesis, it is necessary to simultaneously demonstrate (1) a correlation between amyloid deposition and brain atrophy volume, and (2) that there are changes in actual brain volumes, and not merely in relative ratios.

Next, we will discuss the possibility that lecanemab accelerated neurodegeneration, thereby producing a genuine reduction in brain tissue volume. Alves et al. reported that anti-Aβ agents affect brain volume; notably, they showed that amyloid-related imaging abnormalities-inducing monoclonal antibodies such as lecanemab reduce whole-brain volume, together with a more pronounced enlargement of the lateral ventricles.²⁶ As discussed above, if the post-lecanemab treatment brain volume reduction was attributable to Aβ removal, a clear inconsistency emerges, i.e., amyloid is concentrated predominantly in gray matter, whereas ventricular enlargement is generally interpreted as a marker of white-matter. If the observed reduction in brain volume is not attributable to Aβ removal, an alternative explanation is that lecanemab injures brain tissue and thereby accelerates atrophy—an interpretation that warrants careful consideration. Consistent with this view, Høilund-Carlsen et al. suggested that decreases in amyloid-PET signals after lecanemab treatment may reflect therapy-associated tissue damage rather than plaque removal.²⁷ However, if lecanemab was causing structural brain injury, a worsening in patient cognition is expected to occur, which appears to conflict with the clinical findings that lecanemab attenuates deterioration on the CDR – Sum of Boxes (SB).¹⁰ However, because the CDR-SB evaluates a relatively narrow set of cognitive domains, it remains possible that this scale lacks the sensitivity to detect the effects of lecanemab-associated brain injury.

Thus, the following two mutually opposing mechanisms remain under consideration for the brain volumetric reductions observed upon lecanemab treatment: (1) the decrease occurs secondary to amyloid removal, and (2) the decrease is caused by drug-induced tissue injury. Importantly, it remains unclear how lecanemab-associated volume decrease is associated with patients’ clinical trajectories. To more accurately characterize lecanemab's effects on brain tissue, additional longitudinal studies are needed, specifically those that investigate the association between the magnitude of brain volume decrease and the course of cognitive function.

Limitations

This study has several limitations. First, the study was conducted in a single dementia specialist clinic, resulting in a relatively small number of enrolled patients. Second, although the MRI scans obtained after the fourth administration of lecanemab were consistently performed using a 3T scanner, those acquired prior to the first administration were a mix of 1.5T and 3T scans. Therefore, it cannot be ruled out that differences in magnetic field strength may have affected the imaging analysis results. However, previous studies have demonstrated that there are no significant differences in VSRAD results between 1.5T and 3T MRI.^28,29 Indeed, even when the analysis was limited to patients whose baseline MRI prior to the first lecanemab administration was performed using a 3T scanner, a significant reduction in the Z-score of MTL and the MTL/whole brain ratio was observed following lecanemab treatment. Third, this study did not involve direct volumetric measurements. For a more accurate assessment, measurements of whole brain, hippocampal, and ventricular volumes is necessary. Nevertheless, this study remains valuable in that it aimed to evaluate the effects of lecanemab using VSRAD, a tool that can be relatively easily implemented in routine clinical practice. The incorporation of whole brain, hippocampal, and ventricular volume measurements should be considered in future studies. Fourth, in this study, the Z-score of MTL was assessed at two time points; i.e., before the initial administration and after the fourth administration of lecanemab. To more accurately capture the trajectory of change, additional evaluations at three or more time points would be desirable. Future studies should hence incorporate such multi-timepoint assessments to more acurately characterize longitudinal changes.

Conclusion

In this study, we demonstrated that the Z-score of MTL, as assessed using VSRAD, was significantly reduced in AD patients who underwent four biweekly administrations of lecanemab in real-world clinical settings. This observation suggests that lecanemab may reduce brain volume in patients with AD within a relatively short time frame. However, it remains unclear as to how these reductions in brain volume affect the clinical course of patients treated with lecanemab. Accordingly, further longitudinal studies are warranted to clarify the association between brain volume reduction and clinical outcomes, including cognitive function.

Footnotes

Acknowledgements

We would like to thank Helena Akiko Popiel of the Center for International Education and Research of Tokyo Medical University for reviewing the manuscript.

ORCID iDs

Yuta Inagawa

Shoya Inagawa

Tomohiko Sato

Mana Yoshimura

Kazuhiro Saito

Haruo Hanyu

Soichiro Shimizu

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tokyo Medical University (no. T2025-0018) on May 07, 2025, with the need for written informed consent waived.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Author contribution(s)

Yuta Inagawa: Formal analysis; Investigation; Writing – original draft.

Tomoki Kamiya: Formal analysis; Investigation; Writing – original draft.

Yuki Miyagi: Formal analysis; Investigation; Writing – original draft.

Shoya Inagawa: Formal analysis; Investigation; Writing – original draft.

Naoto Takenoshita: Methodology; Writing – original draft.

Tomohiko Sato: Methodology; Writing – original draft.

Mana Yoshimura: Methodology; Supervision; Writing – review & editing.

Kazuhiro Saito: Methodology; Supervision; Writing – review & editing.

Haruo Hanyu: Conceptualization; Supervision; Writing – review & editing.

Soichiro Shimizu: Conceptualization; Supervision; Writing – review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

As the data includes personal information of the patients, it cannot be made publicly available in its entirety. We have uploaded the minimum anonymized data necessary to reproduce the research. (DOI: 10.6084/m9.figshare.28105724)

References

Baron

Chételat

Desgranges

, et al. In vivo mapping of gray matter loss with voxel-based morphometry in mild Alzheimer's disease. Neuroimage 2001; 14: 298–309.

Matsuda

Kitayama

Ohnishi

, et al. Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer's disease. J Nucl Med 2002; 43: 304–311.

Ohnishi

Matsuda

Tabira

, et al.

Changes in brain morphology in Alzheimer disease and normal aging: is Alzheimer disease an exaggerated aging process?

AJNR Am J Neuroradiol 2001; 22: 1680–1685.

Matsuda

. Voxel-based morphometry of brain MRI in normal aging and Alzheimer's disease. Aging Dis 2013; 4: 29–37.

Matsuda

Mizumura

Nemoto

, et al. Automatic voxel-based morphometry of structural MRI by SPM8 plus diffeomorphic anatomic registration through exponentiated lie algebra improves the diagnosis of probable Alzheimer disease. AJNR Am J Neuroradiol 2012; 33: 1109–1114.

Takechi

Saito

, et al. A comparative study: visual rating scores and the voxel-based specific regional analysis system for Alzheimer's disease on magnetic resonance imaging among subjects with Alzheimer's disease, mild cognitive impairment, and normal cognition. Psychogeriatrics 2019; 19: 95–104.

Hirata

Matsuda

Nemoto

, et al. Voxel-based morphometry to discriminate early Alzheimer's disease from controls. Neurosci Lett 2005; 382: 269–274.

Matsuda

. MRI Morphometry in Alzheimer's disease. Ageing Res Rev 2016; 30: 17–24.

Watanabe-Nakayama

Tsuji

Umeda

, et al. Structural dynamics of amyloid-β protofibrils and actions of anti-amyloid-β antibodies as observed by high-speed atomic force microscopy. Nano Lett 2023; 23: 6259–6268.

10.

van Dyck

Swanson

Aisen

, et al. Lecanemab in early Alzheimer's disease. N Engl J Med 2023; 388: 9–21.

11.

McKhann

Knopman

Chertkow

, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 263–269.

12.

Properzi

Buckley

Chhatwal

, et al. Nonlinear distributional mapping (NoDiM) for harmonization across amyloid-PET radiotracers. Neuroimage 2019; 186: 446–454.

13.

Klunk

Koeppe

Price

, et al. The centiloid project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement 2015; 11: 1–15.e11–14.

14.

Shoji

Matsubara

Kanai

, et al. Combination assay of CSF tau, A beta 1-40 and A beta 1-42(43) as a biochemical marker of Alzheimer's disease. J Neurol Sci 1998; 158: 134–140.

15.

Lewczuk

Esselmann

Otto

, et al. Neurochemical diagnosis of Alzheimer's dementia by CSF Abeta42, Abeta42/Abeta40 ratio and total tau. Neurobiol Aging 2004; 25: 273–281.

16.

Sugioka

Suzumura

Kuno

, et al. Relationship between finger movement characteristics and brain voxel-based morphometry. PLoS One 2022; 17: e0269351.

17.

Boldrini

Fulmore

Tartt

, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 2018; 22: 589–599.e585.

18.

Spalding

Bergmann

Alkass

, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013; 153: 1219–1227.

19.

Sperling

Jack Jr

Black

, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's association research roundtable workgroup. Alzheimers Dement 2011; 7: 367–385.

20.

Thal

Rüb

Orantes

, et al. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58: 1791–1800.

21.

Swanson

Zhang

Dhadda

, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-aβ protofibril antibody. Alzheimers Res Ther 2021; 13: 80.

22.

Belder

CRS

Boche

Nicoll

JAR

, et al. Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related pseudo-atrophy. Lancet Neurol 2024; 23: 1025–1034.

23.

Fjell

McEvoy

Holland

, et al. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus. Prog Neurobiol 2014; 117: 20–40.

24.

Roberts

Lind

Wagen

, et al. Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET. Brain 2017; 140: 1486–1498.

25.

Ayton

. Brain volume loss due to donanemab. Eur J Neurol 2021; 28: e67–e68.

26.

Alves

Kalinowski

Ayton

. Accelerated brain volume loss caused by anti-β-amyloid drugs: a systematic review and meta-analysis. Neurology 2023; 100: e2114–e2124.

27.

Høilund-Carlsen

Revheim

Costa

, et al.

Passive Alzheimer's immunotherapy: a promising or uncertain option?

Ageing Res Rev 2023; 90: 101996.

28.

Briellmann

Syngeniotis

Jackson

. Comparison of hippocampal volumetry at 1.5 tesla and at 3 tesla. Epilepsia 2001; 42: 1021–1024.

29.

Sone

Imabayashi

Maikusa

, et al. Voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) on 3-tesla normal database: diagnostic accuracy in two independent cohorts with early Alzheimer's disease. Aging Dis 2018; 9: 755–760.