Retrospective Cohort Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2025; 16(8): 106664
Published online Aug 15, 2025. doi: 10.4239/wjd.v16.i8.106664
Higher glycated hemoglobin amplifies the effect of apolipoprotein E epsilon 4-related cognition and olfaction impairments in type 2 diabetes
Ya-Rong Wang, Yang Gao, Yan-Chao Liu, Zhi-Peng Xu, Yu-Ying Wang, Hai-Bo Xu, Jian-Zhi Wang, Yao Zhang
Ya-Rong Wang, Yao Zhang, Department of Endocrinology, Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, Hubei Province, China
Yang Gao, Hai-Bo Xu, Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei Province, China
Yan-Chao Liu, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Zhi-Peng Xu, Yu-Ying Wang, Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Jian-Zhi Wang, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Co-first authors: Ya-Rong Wang and Yang Gao.
Co-corresponding authors: Jian-Zhi Wang and Yao Zhang.
Author contributions: Zhang Y, Wang JZ designed the research and wrote the manuscript; Wang YR, Gao Y, Liu YC, Xu ZP, Wang YY, Xu HB recruited the patients and collected blood samples; Wang YR and Gao Y performed the experiments, performed the statistical analysis; Wang YR contributed to data interpretation and manuscript editing; Zhang Y and Wang JZ was the guarantor of this work and has full access to all the data in the study, and took responsibility for the integrity of the data and accuracy of the data analysis; All authors read and approved the final manuscript.
Supported by the China Postdoctoral Science Foundation General Program, No. 2024M762504; and the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 2023 LYYYGZRP0004.
Institutional review board statement: The Medical Ethics Committee approved the study protocol (No. 2013-S071), Tongji Medical College, Huazhong University of Science and Technology.
Informed consent statement: All participants had provided written informed consent.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
STROBE statement: The authors have read the STROBE Statement—a checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-a checklist of items.
Data sharing statement: All data are available in the manuscript or the supplementary materials. Other data supporting the findings of this study are available from the corresponding author, prof. Zhang Y (zhangyaodoc@163.com), upon request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yao Zhang, Doctor, Department of Endocrinology, Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Qiaokou District, Wuhan 430077, Hubei Province, China. zhangyaodoc@163.com
Received: March 4, 2025
Revised: April 30, 2025
Accepted: July 4, 2025
Published online: August 15, 2025
Processing time: 163 Days and 8.8 Hours
Abstract
BACKGROUND

Apolipoprotein E epsilon 4 (APOE4) is recognized as a genetic risk factor for cognitive decline and neurodegeneration in both type 2 diabetes mellitus (T2DM) and Alzheimer’s disease, while glycated hemoglobin (HbA1c) reflects persistent hyperglycemia and serves as a key indicator of long-term glycemic control in T2DM. Although both factors have been individually linked to neurobehavioral deficits, it remains uncertain whether HbA1c contributes to APOE4-related cognitive and olfactory impairment in individuals with T2DM.

AIM

To investigate the role of HbA1c in APOE4-associated cognitive and olfactory dysfunction in patients with T2DM.

METHODS

Of 636 T2DM patients were recruited from five medical centers in Wuhan, Hubei Province, China. APOE genotyping was evaluated by polymerase chain reaction using Gerard’s method. Cognitive and olfactory functions were assessed by mini-mental state examination and Connecticut chemosensory clinical research center test, respectively. Regression analysis was employed to assess the independent and interactive effects of HbA1c on APOE4-associated cognitive and olfactory function.

RESULTS

APOE4 was associated with increased risks of cognitive impairment [odds ratios (OR) = 1.815, P = 0.021] and olfactory dysfunction (OR = 2.588, P < 0.001). Higher HbA1c levels were also related to worse cognitive (OR = 1.189, P < 0.001) and olfactory performance (OR = 1.149, P = 0.011). HbA1c exerted a moderating effect, yet not a mediating effect, between APOE4 and its impacts on cognition and olfaction. Specifically, a higher level of HbA1c exacerbated the damaging effect of APOE4, as shown by significant interaction effects on both cognitive impairment (OR = 2.687, P < 0.001) and olfactory dysfunction (OR = 1.440, P = 0.027).

CONCLUSION

Elevated HbA1c levels are associated with increased risks of cognitive and olfactory impairments in patients with T2DM and may exacerbate the detrimental effects of APOE4. These findings underscore the need for early preventive strategies targeting individuals with both poor glycemic control and APOE4 carriage to mitigate neurodegenerative risk.

Keywords: Glycated hemoglobin; Apolipoprotein E epsilon 4; Type 2 diabetes mellitus; Cognitive impairment; Olfactory function

Core Tip: This study explores how the apolipoprotein E epsilon 4 (APOE4) genotype and glycated hemoglobin (HbA1c) levels influence cognitive and olfactory performance in individuals with type 2 diabetes mellitus. The findings suggest that APOE4 is linked to both cognitive and olfactory deficits, and that elevated HbA1c levels further intensify these effects. Rather than serving as a mediator, HbA1c modifies the relationship, strengthening the adverse impact of APOE4. These results indicate that both APOE4 and poor glycemic control contribute to neurofunctional decline, underscoring the importance of early intervention in at-risk diabetic populations.