
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38728857
IJS-D-24-01730
10.1097/JS9.0000000000001611
00058
3
Correspondence
Letter to the Editor: Limitations of acetylcholinesterase inhibitor therapy for Alzheimer’s disease
Yang Guang MD a934971779@qq.com

Wu Jiawen MD 627522950@qq.com
a
Lei Hang MD bleihang@stu.scu.edu.cn

Hui Yining MD c*hyn1573@163.com

a Department of Neurology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan
b Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan
c Southwest Medical University, Luzhou, People’s Republic of China
* Corresponding author. Address: Southwest Medical University, Luzhou 646000, People’s Republic of China. Tel.: +86 193 827 406 74. E-mail: hyn1573@163.com (Y. Hui).
9 2024
10 5 2024
110 9 58525853
26 4 2024
29 4 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

OPEN-ACCESSTRUE
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pmc Dear Editor,

The management and treatment of Alzheimer’s disease (AD) patients are significant challenges globally. Acetylcholinesterase inhibitors (AChEIs) have long been the main treatment for AD, functioning by inhibiting the activity of acetylcholinesterase, slowing the breakdown of acetylcholine, and thereby increasing the concentration of acetylcholine in the brain. Since acetylcholine is a crucial neurotransmitter involved in memory and learning processes, this mechanism helps to improve or stabilize the cognitive functions and daily living abilities of AD patients. However, the efficacy of AChEIs has been highly controversial in recent years. Although the clinical efficacy of AChEIs has been confirmed through phase 3 randomized double-blind controlled trials (RCTs) targeting mild to moderate AD patients and typically less than one year of follow-up, the real-world effectiveness of AChEIs remains questioned1. This urgently demands precise studies on the efficacy of AChEIs.

We reviewed a study published by Zhang et al.2 on the effectiveness of AChEIs in treating AD patients. They conducted a meta-analysis including several randomized, double-blind controlled trials and found significant improvements in the AD Assessment Scale (ADAS), Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus), and the Neuropsychiatric Inventory (NPI), concluding that AChEIs are effective in treating AD patients. This highlights the critical role and importance of AChEIs in AD treatment and provides essential references for clinical decision-making by healthcare professionals.

However, this study still has several limitations that need to be highlighted for comprehensive reference by healthcare decision-makers. Firstly, the study was limited to AChEIs as interventions without considering the heterogeneity in study designs, participant characteristics, severity of dementia, and variations in the dosages and types of AChEIs used across studies. This could affect the generalizability and applicability of the results, leading to skewed findings and potentially misleading subsequent researchers3. Additionally, although the authors mentioned that the symmetry of the funnel plot suggests a lower risk of publication bias, the inherent limitations of the funnel plot, including its insensitivity in detecting bias in meta-analyses with a small number of studies, should also be acknowledged.

Secondly, the report points out that although AChEIs generally improved various neuropsychiatric and functional scores, there was no observed improvement compared to placebo in the Mini-Mental State Examination (MMSE), the Clinician Interview-Based Impression of Severity (CIBIS), and ADCS-ADL scores; in fact, the Alzheimer Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scores even deteriorated. This is surprising, and the worsening indicators highlight the instability of the study results, indicating substantial potential risks in the authors’ conclusions. The authors should conduct an in-depth analysis of these outcomes, discussing their potential mechanisms and clinical impacts in detail. Subgroup or regression analysis may help identify factors causing these variations, and authors need to clarify these using controlled methods, as these differences could influence the outcome changes.

Lastly, the meta-analysis indicates that AChEIs do not increase the risk of severe adverse events compared to placebo, which is an important finding in clinical practice. However, AChEIs showed more pronounced gastrointestinal side effects than placebo, which could affect patient compliance and quality of life, particularly as Alzheimer’s disease patients already have higher healthcare management needs. A more detailed discussion on the balance between benefits and side effects, possibly including patient-centered outcomes, would provide more comprehensive information.

Future research should validate the effects of AChEIs in a broader and more diverse patient population and explore the potential additional benefits of combining them with other therapies. Moreover, considering individual differences in treatment response to AChEIs, future studies should take into account patients’ genetic backgrounds, stages of disease progression, and other health conditions to develop more precise and personalized treatment strategies4. Through these efforts, we can look forward to new advances in the management and treatment of Alzheimer’s disease.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This research was supported by the Kunshan Key Research and Development Program (Social Development) Project Fund (KS2325).

Author contribution

G.Y., J.W., H.L., and Y.H.: conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing – original draft, writing – review and editing, supervision, and project administration.

Conflicts of interest disclosure

There are no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Guang Yang, Jiawen Wu, Hang Lei, and Yining Hui.

Data availability statement

The data used to support the findings of this study are included within the article.

Provenance and peer review

Not applicable.

Acknowledgements

Assistance with the study: none.

Guang Yang, Jiawen Wu, and Hang Lei, contributed equally to this work.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 10 May 2024
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References

1 Zuliani G Zuin M Romagnoli T . Acetyl-cholinesterase-inhibitors reconsidered. A narrative review of post-marketing studies on Alzheimer’s disease. Aging Clin Exp Res 2024;36 :23.38321321
2 Zhang Y Sun Y Hu X . The value of cholinesterase inhibitors for improving neuropsychiatric and functional assessment scores in patients with alzheimer disease: a systematic review and meta-analysis of on placebo-controlled RCTs. Int J Surg (London, England) 2024;Apr 3 [Epub ahead of print]. doi:10.1097/JS9.0000000000001381
3 Moreira NC Lima JE Marchiori MF . Neuroprotective effects of cholinesterase inhibitors: current scenario in therapies for Alzheimer’s disease and future perspectives. J Alzheimers Dis Rep 2022;6 :177–193.35591949
4 Xu J Gou S Huang X . Uncovering the impact of aggrephagy in the development of Alzheimer’s disease: insights into diagnostic and therapeutic approaches from machine learning analysis. Curr Alzheimer Res 2023;20 :618–635.38141185
