This prospective study was conducted at Yasu City Hospital. Participants were enrolled based on the following neuropsychological and cerebrospinal fluid (CSF) biomarker criteria: Mini-Mental State Examination (MMSE) score between 22 and 28, Montreal Cognitive Assessment (MoCA) score between 18 and 25, Clinical Dementia Rating-Global Score (CDR-GS) between 0.5 and 1, and Geriatric Depression Scale (GDS) score of 8 or lower. CSF biomarkers included an amyloid-β 1–42 to 1–40 ratio (Aβ42/40 ratio) of 0.67 or lower and phosphorylated tau 181 (p-tau181) of 59.0 pg/mL or higher. For a more detailed assessment of cognitive function, the CDR-Sum of Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were also administered (Table 1).

All participants were screened using structural MRI, including T1-weighted, FLAIR, SWI, and time-of-flight MRA sequences. We excluded individuals with any evidence of large territorial infarction, intracerebral hemorrhage, intracranial mass lesions, or significant asymmetry or stenosis in the internal carotid artery system.

The study included 8 participants (6 females and 2 males) aged between 60 and 79 years. Each participant received lecanemab infusions every 2 weeks, and evaluations were conducted between 6 months and 1 year after the initiation of treatment.

This prospective observational study was approved by the Ethics Committee of Yasu City Hospital. As the study involved only the analysis of data obtained during routine clinical care, and posed no additional risk or burden to participants, the requirement for written informed consent was waived in accordance with institutional ethical guidelines.

All MRI data were collected using a 3 T MRI system (Lumina; Siemens, Erlangen, Germany), equipped with a 32-channel head coil. Structural 3D T1-weighted images were acquired using three-dimensional magnetization-prepared rapid gradient-echo (3D-MPRAGE) sequences with the following parameters: repetition time (TR) = 1,240 ms, echo time (TE) = 2.88 ms, inversion time (TI) = 900 ms, flip angle (FA) = 10°, field of view (FOV) = 256 × 256 mm, resolution 1 × 1 × 2 mm³. ASL images were acquired by employing 3D fast spin echo pseudo-continuous ASL (pCASL) sequence with acquisition parameters: TR = 4,500 ms, TE = 21.80 ms, FA = 120°, voxel size = 1.8 × 1.8 × 5 mm³, NEX = 3 and post label delay = 2,000 ms. For the WM microstructural evaluation, a standard DTI protocol was performed with the following parameters TR = 10,800 ms, TE = 108 ms, voxel size = 2 × 2 × 2 mm³, gap = 0, 30 diffusion directions with b = 1,500 s/mm².

All participants underwent MRI scans before the initiation of lecanemab treatment, with follow-up scans conducted at the 13th (6 months), 20th (9 months), and 26th (1 year) administrations after treatment initiation. At each time point, imaging was performed using 3D T1-weighted images, pCASL, and DTI sequences to analyze longitudinal changes in brain volume, CBF, gray matter microstructure and white matter microstructure.

All MRI data in DICOM format were converted to NIfTI format using dcm2niix (version 1.0.20240202) (Li et al., 2016). T1-weighted images underwent bias field correction, skull stripping, and tissue segmentation using the fsl_anat tool from FSL (version 6.0.7.13) (Smith et al., 2004). ASL images were processed using the BASIL module (oxford_asl) based on a Bayesian inference model (Chappell et al., 2009), and CBF maps were generated.

DTI data were processed using topup (Andersson et al., 2003), eddy (Andersson et al., 2018; Andersson et al., 2017; Andersson et al., 2016; Andersson and Sotiropoulos, 2016), and DTIFIT, all of which are part of FSL, to correct for magnetic field and eddy current distortions and to compute voxel-wise diffusion measures such as FA and MD. DTI analysis was performed using the standard pipeline provided by FSL.

To enable integrated analysis within the same spatial framework, ASL and DTI data were accurately registered to FreeSurfer space using bbregister from FreeSurfer (version 8.0.0). Longitudinal processing in FreeSurfer was applied to improve within-subject consistency across timepoints. Brain volume measures were obtained from FreeSurfer (Fischl et al., 2002), while CBF, FA, and MD values derived from FSL were resampled into the same space. ROI analyses targeted the hippocampus, posterior cingulate cortex and precuneus, which are key regions along the Alzheimer’s disease continuum and were defined anatomically using FreeSurfer.

The results of the statistical analysis of neuropsychological tests are presented in Figure 1. No significant changes were observed in the neuropsychological test scores, except for ADAS-J Cog at the 12-month time point, which showed a significant improvement.

The results of the statistical analysis of CSF biomarkers are presented in Figure 2. Significant improvements were observed in Aβ42, Aβ42/40 ratio, and p-tau181 at both the 6-month and 12-month time points.

The results of the statistical analysis of whole-brain measures are presented in Figure 3. Whole-brain volume showed a significant decrease at 6, 9, and 12 months compared to baseline. Whole-brain CBF did not show any significant changes at any follow-up time point. Whole-brain FA showed a significant decrease, and whole-brain MD showed a significant increase at 6, 9, and 12 months compared to baseline.

The results of the statistical analysis of hippocampal measures are presented in Figure 4 for the left hippocampus and Figure 5 for the right hippocampus. Hippocampal volume showed a significant decrease at 6, 9, and 12 months compared to baseline. Hippocampal CBF showed no significant changes at 6, 9, or 12 months. Hippocampal FA also showed no significant changes at 6, 9, or 12 months. Although the decrease in right hippocampal FA at 12 months did not reach statistical significance (p = 0.0547), the effect size was large (r = −0.679), suggesting a meaningful trend of microstructural deterioration. Hippocampal MD showed a significant increase at 6, 9 and 12 months except for the left hippocampus at 9 months. Although the increase at 9 months in left hippocampal did not reach statistical significance (p = 0.0547), the effect size was large (r = 0.679), suggesting a consistent and meaningful trend of microstructural deterioration over time.

The results of the statistical analysis of posterior cingulate cortex measures are presented in Figure 6 for the left posterior cingulate cortex and Figure 7 for the right posterior cingulate cortex. Posterior cingulate cortex volume showed a significant decrease at 6, 9, and 12 months compared to baseline. Posterior cingulate cortex CBF showed no significant changes at 6, 9, or 12 months. Posterior cingulate cortex FA also showed no significant changes at 6, 9, or 12 months. Posterior cingulate cortex MD showed no significant changes at 6, 9, or 12 months except for the left posterior cingulate cortex at 6 months, which showed a significant increase.

The results of the statistical analysis of precuneus measures are presented in Figure 8 for the left precuneus and Figure 9 for the right precuneus. Precuneus volume showed a significant decrease at 6, 9, and 12 months compared to baseline. Precuneus CBF showed no significant changes at 6, 9, or 12 months. Precuneus FA showed no significant changes at 6, 9, or 12 months except for the right precuneus at 12 months, which showed a significant decrease. Left precuneus MD showed a significant increase at 6 and 9 months. Although the increase at 12 months in left precuneus MD did not reach statistical significance (p = 0.0547), the effect size was large (r = −0.679), suggesting a consistent and meaningful trend of microstructural deterioration over time. Right precuneus MD showed no significant changes at 6, 9, or 12 months. Although the increase at 6 months in right precuneus did not reach statistical significance (p = 0.0547), the effect size was large (r = 0.679), suggesting a meaningful trend of microstructural deterioration.

To further investigate, we analyzed the cingulum bundle, a white matter tract that anatomically connects the hippocampus, posterior cingulate cortex, and precuneus. The results of the statistical analysis of cingulum measures are presented in Figure 10 for the cingulum (cingulate gyrus) and in Figure 11 for the cingulum (hippocampus), both defined according to the JHU white matter atlas from FSL. The cingulum (cingulate gyrus) showed a significant increase in MD at 12 months compared to baseline, whereas the cingulum (hippocampus) showed no significant changes. These findings may suggest progressive microstructural alterations during lecanemab treatment.

In this exploratory longitudinal study of patients with MCI receiving lecanemab, we observed progressive reductions in brain volume—including whole brain, hippocampus, posterior cingulate cortex, and precuneus—over a 6-to-12-month treatment period. In contrast, CBF remained stable across all examined regions. DTI measures revealed a more heterogeneous pattern: MD increased in the whole brain, the bilateral hippocampus, the left precuneus, and the cingulum (cingulate gyrus), while FA remained relatively stable in regions closely associated with cognitive function. Notably, cognitive performance did not show significant deterioration, while significant improvements were observed in Aβ42, the Aβ42/40 ratio, and p-tau181 over the course of the study.

While alterations in CBF, including both decreases and transient increases, have been reported during the MCI stage of Alzheimer’s disease, the absence of significant change in our cohort may reflect hemodynamic stability during lecanemab treatment (Alsop et al., 2010; Binnewijzend et al., 2016). This stability was observed even in regions such as the posterior cingulate cortex and precuneus, which are among the earliest to exhibit CBF reduction in the prodromal stage of Alzheimer’s disease (Alsop et al., 2010; Binnewijzend et al., 2016). These findings suggest that lecanemab may help stabilize vascular and metabolic function in the early stages of disease progression.

With respect to gray matter microstructure and white matter microstructure, our findings revealed a dissociation between FA and MD trajectories. FA remained relatively stable in key regions such as the hippocampus, posterior cingulate cortex, precuneus, and the cingulum (cingulate gyrus), while MD showed significant increases primarily in the bilateral hippocampus, left precuneus, and the cingulum (cingulate gyrus). This pattern is consistent with previous studies suggesting that MD may be more sensitive than FA in detecting early microstructural alterations along the Alzheimer’s disease continuum (Nir et al., 2013; Niu et al., 2023).

Previous studies have demonstrated associations between DTI measures and cognitive performance in individuals with Alzheimer’s disease and MCI (Chen et al., 2023; Nir et al., 2013). In this context, the relative preservation of FA in regions implicated in memory and higher-order cognitive functions, such as the hippocampus, posterior cingulate cortex, and precuneus, may at least partly account for the stable cognitive profiles observed in the present cohort. Although causality cannot be inferred, the partial preservation of gray matter microstructure and white matter integrity in these areas may contribute to the maintenance of cognitive function despite concurrent volume loss and MD increases. These findings emphasize the value of integrating diffusion imaging with structural and perfusion measures to better understand the multifaceted nature of disease progression and treatment response.

The hippocampus, precuneus, and posterior cingulate cortex are among the regions vulnerable to early alterations in Alzheimer’s disease (Alsop et al., 2010; Buckner et al., 2005; Chen et al., 2023; Frisoni et al., 2010). In the present study, all three regions showed progressive volume loss. Changes in MD were observed primarily in the hippocampus, left precuneus, and the cingulum (cingulate gyrus), where MD increased in parallel with volume reduction, while CBF and FA remained relatively stable. This discrepancy between structural degeneration and preserved perfusion or axonal integrity may represent an intermediate stage of disease progression. These findings suggest that regional assessment of volume, MD, CBF, and FA may provide sensitive markers of treatment response in MCI patients receiving lecanemab.

Several limitations of this study should be acknowledged. First, the small sample size (n = 8) limits statistical power and increases the risk of both Type I and Type II errors. The absence of a control group further restricts the ability to isolate treatment effects from the natural course of disease progression. In addition, multiple comparisons were performed without correction due to the exploratory nature of the study, which necessitates cautious interpretation of the findings. Moreover, the sex distribution of participants was unbalanced (6 females and 2 males), which may have amplified individual variability and limited the generalizability of the findings. Finally, as all participants were recruited from a single site in Japan, potential differences related to ethnic, genetic, or environmental backgrounds should be considered when generalizing these findings to non-Asian populations. These limitations underscore the need for larger, controlled studies to validate and extend the present observations.