Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels
Kangli Dong,
Wei Liang,
Ting Hou,
Zhijie Lu,
Yixuan Hao,
Chenrui Li,
Yue Qiu,
Nan Kong,
Yan Cheng,
Yaqi Wen,
Wanyin Ma,
Wenbin Zheng,
Jitian Guan,
Yan Lin,
Kai Huang,
Lu Zhang,
Siya Chen,
Xiangyuan Ma,
Renhua Wu,
Naili Wei
Affiliations
Kangli Dong
Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, China
Wei Liang
Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, China
Ting Hou
Department of Human Anatomy and Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
Zhijie Lu
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
Yixuan Hao
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
Chenrui Li
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
Yue Qiu
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
Nan Kong
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
Yan Cheng
The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
Yaqi Wen
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Wanyin Ma
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Wenbin Zheng
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Jitian Guan
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Yan Lin
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Kai Huang
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China
Lu Zhang
Department of Rehabilitation, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310027, Zhejiang, China
Siya Chen
Department of Computer Science, City University of Hong Kong, Hong Kong, 999077, Hong Kong, China
Xiangyuan Ma
Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, China; Corresponding authors.
Renhua Wu
Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China; Corresponding authors.
Naili Wei
Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China; Corresponding authors.
The apolipoprotein E (APOE) ɛ4 allele is a recognized genetic risk factor for Alzheimer’s Disease (AD). Studies have shown that APOE ɛ4 mediates the modulation of intrinsic functional brain networks in cognitively normal individuals and significantly disrupts the whole-brain topological structure in AD patients. However, how APOE ɛ4 regulates brain functional connectivity (FC) and consequently affects the levels of cognitive impairment in AD patients remains unknown. In this study, we systematically analyzed functional magnetic resonance imaging (fMRI) data from two distinct cohorts: an In-house dataset includes 59 AD patients (73.37 ± 6.42 years), and the ADNI dataset includes 117 AD patients (74.91 ± 7.91 years). Experimental comparisons were conducted by grouping AD patients based on both APOE ɛ4 status and cognitive impairment levels of AD. Network-Based Statistic (NBS) method and the Graph Neural Network Explainer (GNN-Explainer) were combined to identify significant FC changes across different comparisons. Importantly, the GNN-Explainer method was introduced as an enhancement over the NBS method to better model complex high-order nonlinear characteristics for discovering FC features that significantly contribute to classification tasks. The results showed that APOE ɛ4 primarily influenced temporal lobe FCs, while it influenced different cognitive impairment levels of AD by adjusting prefrontal-parietal FCs. These findings were validated by p-values < 0.05 from NBS method, and 5-fold cross-validation along with ablation studies from the GNN-Explainer method. In conclusion, our findings provide new insights into the role of APOE ɛ4 in altering FC dynamics during the progression of AD, highlighting potential targets for early intervention.
