Dear Editor,
The recent article by Nakashima et al., “Therapeutic Time Window of Disease‐Modifying Therapy for Early Alzheimer's Disease in Japanese Individuals: Analysis Based on J‐ADNI Study,” provides valuable insights into predictors of the therapeutic eligibility window for lecanemab and donanemab among Japanese individuals with early Alzheimer's disease [1]. The study addresses an important clinical challenge in the era of disease‐modifying therapies and offers meaningful evidence to support treatment prioritization under resource‐constrained healthcare settings. While the findings are both timely and clinically relevant, several methodological aspects merit further discussion to facilitate a more balanced interpretation of the results.
Although the study utilizes the well‐established Japanese Alzheimer's Disease Neuroimaging Initiative (J‐ADNI) database, its findings may have limited external validity because J‐ADNI participants represent a highly selected research population rather than routine clinical practice. Participants enrolled in ADNI studies are typically recruited from specialized academic centers, have higher educational levels, fewer medical comorbidities, better healthcare access, and greater motivation to participate in longitudinal research than the general population. The estimated therapeutic time window reported in this study may overestimate the duration of treatment eligibility in real‐world patients, who often present with more complex clinical profiles, multiple comorbidities, and greater functional impairment [2].
The methodology used in this study may overestimate the actual duration of treatment eligibility because it did not include important clinical exclusion criteria recommended in the Appropriate Use Recommendations (AURs) for lecanemab and donanemab, such as cerebral microhemorrhages, superficial siderosis, severe white matter disease, anticoagulant use, and other MRI findings associated with an increased risk of amyloid‐related imaging abnormalities (ARIA) [3]. Also, the reported therapeutic window reflects cognitive eligibility based primarily on MMSE and CDR‐GS rather than actual clinical eligibility for treatment. Participants were assessed only at 6 or 12 month intervals, meaning that the exact time at which patients became ineligible remains unknown [4]. Although the authors acknowledge both limitations, a more detailed discussion of their potential impact on the study findings would strengthen the manuscript.
The multivariable Cox regression analysis included only a limited number of baseline variables, such as age, sex, MMSE, CDR‐GS, education, APOE ε4 status, and CDR‐SB; other than several clinically relevant factors known to influence Alzheimer's disease progression and treatment eligibility were not considered. Variables such as vascular comorbidities, frailty, depression, medication burden, MRI biomarkers, functional status, and socioeconomic factors may independently affect cognitive decline and the duration of treatment eligibility. The exclusion of these potential confounders raises the possibility of residual confounding, the observed associations between MMSE, CDR‐GS, and the therapeutic time window may be partially influenced by unmeasured variables [5].
In conclusion, this study provides important evidence regarding the therapeutic time window for disease‐modifying therapies in early Alzheimer's disease and offers valuable insights for treatment prioritization in resource‐limited settings. Addressing the methodological considerations, including issues related to cohort representativeness, comprehensive treatment eligibility assessment, interval‐censored follow‐up, and potential residual confounding, would further strengthen the validity and clinical applicability of the findings.
Author Contributions
Suman Pradhan: conceptualization, writing original draft, writing review and editing.
Funding
The author has nothing to report.
Ethics Statement
The author has nothing to report.
Conflicts of Interest
The author declares no conflicts of interest.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
References
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- 5. Livingston G., Huntley J., Liu K. Y., et al., “Dementia Prevention, Intervention, and Care: 2024 Report of the Lancet Standing Commission,” Lancet 404, no. 10452 (2024): 572–628. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.