Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | NeuroImage |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1053811924004488 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kangli Dong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e3657f71f7674559b8d5d9cd75df37b4 |
| institution | Kabale University |
| issn | 1095-9572 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | NeuroImage |
| spelling | doaj-art-e3657f71f7674559b8d5d9cd75df37b42025-01-11T06:38:29ZengElsevierNeuroImage1095-95722025-01-01305120951Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levelsKangli Dong0Wei Liang1Ting Hou2Zhijie Lu3Yixuan Hao4Chenrui Li5Yue Qiu6Nan Kong7Yan Cheng8Yaqi Wen9Wanyin Ma10Wenbin Zheng11Jitian Guan12Yan Lin13Kai Huang14Lu Zhang15Siya Chen16Xiangyuan Ma17Renhua Wu18Naili Wei19Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, ChinaDepartment of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, ChinaDepartment of Human Anatomy and Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, ChinaDepartment of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, ChinaThe Second Hospital of Shandong University, Jinan, 250033, Shandong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, ChinaDepartment of Rehabilitation, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310027, Zhejiang, ChinaDepartment of Computer Science, City University of Hong Kong, Hong Kong, 999077, Hong Kong, ChinaDepartment of Biomedical Engineering, College of Engineering, Shantou University, Shantou, 515063, Guangdong, China; Corresponding authors.Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, Guangdong, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S1053811924004488AlzheimerAPOE ɛ4fMRIFunctional connectivityGraph neural network |
| spellingShingle | 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 Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels NeuroImage Alzheimer APOE ɛ4 fMRI Functional connectivity Graph neural network |
| title | Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels |
| title_full | Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels |
| title_fullStr | Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels |
| title_full_unstemmed | Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels |
| title_short | Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels |
| title_sort | exploring the impact of apoe e4 on functional connectivity in alzheimer s disease across cognitive impairment levels |
| topic | Alzheimer APOE ɛ4 fMRI Functional connectivity Graph neural network |
| url | http://www.sciencedirect.com/science/article/pii/S1053811924004488 |
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