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Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly

  • Hao Shu
  • Yongmei Shi
  • Gang Chen
  • Zan Wang
  • Duan Liu
  • Chunxian Yue
  • B. Douglas Ward
  • Wenjun Li
  • Zhan Xu
  • Guangyu Chen
  • Qi-Hao Guo
  • Jun Xu
  • Shi-Jiang Li
  • Zhijun Zhang
ORIGINAL RESEARCH

Abstract

The apolipoprotein E (APOE) ε4 and ε2 alleles are acknowledged genetic factors modulating Alzheimer’s disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM-related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE ε2, ε3, and ε4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 ε2 carriers, 44 ε3 homozygotes, and 49 ε4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the ε3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the ε4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the ε2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the ε4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles.

Keywords

Apolipoprotein E Episodic memory Alzheimer’s disease Aging Functional connectivity 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81500919, 81420108012, and 91432000), the USA National Institutes of Health (R44AG035405, Brainsymphonics, LLC), and the Key Program for Clinical Medicine and Science and Technology, Jiangsu Province, China (BL2013025 and BL2014077).

We sincerely thank Ms. Lydia Washechek, B.A., for editorial assistance; Dr. Piero G. Antuono, M.D., for neurocognitive assessment instruction; Youming Zheng, Haixia Feng, Hong Zhu, and Xiaofa Huang for subject recruitment; and Min Wang and Xiaohui Chen for technical support related to MRI scanning.

Funding

This study was supported by the National Natural Science Foundation of China (81500919, 81420108012, and 91432000), the USA National Institutes of Health (R44AG035405, Brainsymphonics, LLC), and the Key Program for Clinical Medicine and Science and Technology, Jiangsu Province, China (BL2013025 and BL2014077).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2017_9818_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1293 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hao Shu
    • 1
    • 2
  • Yongmei Shi
    • 1
  • Gang Chen
    • 2
  • Zan Wang
    • 1
  • Duan Liu
    • 1
  • Chunxian Yue
    • 1
  • B. Douglas Ward
    • 2
  • Wenjun Li
    • 2
  • Zhan Xu
    • 2
  • Guangyu Chen
    • 2
  • Qi-Hao Guo
    • 3
  • Jun Xu
    • 4
  • Shi-Jiang Li
    • 2
  • Zhijun Zhang
    • 1
  1. 1.Department of Neurology, Affiliated ZhongDa Hospital, School of MedicineSoutheast UniversityNanjingChina
  2. 2.Department of BiophysicsMedical College of WisconsinMilwaukeeUSA
  3. 3.Department of Neurology, Huashan HospitalFudan UniversityShanghaiChina
  4. 4.Department of NeurologyJiangsu Province Geriatric InstituteNanjingChina

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