Periphery Biomarkers Predicting Conversion of Type 2 Diabetes to Pre-Alzheimer-Like Cognitive Decline: A Multicenter Follow-Up Study

Article type: Research Article

Authors: Liu, Yanchao^{a; b; 1} | He, Benrong^{b; c; 1} | Du, Kai^{d; e} | Zheng, Jie^f | Ke, Dan^b | Mo, Wen^g | Li, Yanni^g | Jiang, Tao^b | Xiong, Rui^b | Sun, Fei^b | Zhao, Shi^h | Wei, Wei^h | Xu, Zhipengⁱ | Zhang, Shujuan^b | Li, Shihong^b | Wang, Xin^b | Zhou, Qiuzhi^b | Ye, Jinwang^b | Liang, Yi^j | Lin, Hao^j | Liu, Yong^{d; e} | Chen, Liangkai^{k; l} | Zhang, Huaqiu^a | Zhang, Yao^{m; *} | Gao, Yang^{b; n; *} | Wang, Jian-Zhi^{a; b; o; *}

Affiliations: [a] Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [b] Department of Pathophysiology, School of Basic Medicine, Ministry of Education Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [c] Department of Emergency of General Hospital of Central Theater Command, Wuhan, China | [d] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China | [e] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China | [f] Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University. Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, China | [g] Health Service Center of Jianghan District, Wuhan, China | [h] Department of Endocrinology, the Central Hospital of Wuhan, Wuhan, China | [i] Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China | [j] Department of Radiology, Wuhan Brain Hospital, Wuhan, China | [k] Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [l] Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [m] Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [n] Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China | [o] Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

Correspondence: [*] Correspondence to: Jian-Zhi Wang, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel./Fax: +086-27-83693883; E-mail: [email protected]; Yang Gao, Department of Pathophysiology, School of Basic Medicine, Ministry of Education Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. E-mail: [email protected] and Yao Zhang, Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:The prevalence of Alzheimer’s disease (AD) is increasing, therefore, identifying biomarkers to predict those vulnerable to AD is imperative. Type 2 diabetes (T2D) serves as an independent risk factor for AD. Early prediction of T2D patients who may be more susceptible to AD, so as to achieve early intervention, is of great significance to reduce the prevalence of AD. Objective:To establish periphery biomarkers that could predict conversion of T2D into pre-AD-like cognitive decline. Methods:A follow-up study was carried out from 159 T2D patients at baseline. The correlations of cognitive states (by MMSE score) with multi-periphery biomarkers, including APOE genotype, plasma amyloid-β level, platelet GSK-3β activity, and olfactory score were analyzed by logistic regression. ROC curve was used for establishing the prediction model. Additionally, MRI acquired from 38 T2D patients for analyzing the correlation among cognitive function, biomarkers and brain structure. Results:Compared with the patients who maintained normal cognitive functions during the follow-up period, the patients who developed MCI showed worse olfactory function, higher platelet GSK-3β activity, and higher plasma Aβ42/Aβ40 ratio. We conducted a predictive model which T2D patients had more chance of suffering from pre-AD-like cognitive decline. The MRI data revealed MMSE scores were positively correlated with brain structures. However, platelet GSK-3β activity was negatively correlated with brain structures. Conclusions:Elevated platelet GSK-3β activity and plasma Aβ42/Aβ40 ratio with reduced olfactory function are correlated with pre-AD-like cognitive decline in T2D patients, which used for predicting which T2D patients will convert into pre-AD-like cognitive decline in very early stage.

Keywords: Alzheimer’s disease, biomarker, brain structure, mild cognitive impairment, prediction model, type 2 diabetes

DOI: 10.3233/JAD-240455

Journal: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024