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

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.

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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).

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Correspondence to Shi-Jiang Li or Zhijun Zhang.

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Shu, H., Shi, Y., Chen, G. et al. Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly. Brain Imaging and Behavior 13, 255–269 (2019). https://doi.org/10.1007/s11682-017-9818-4

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Keywords

  • Apolipoprotein E
  • Episodic memory
  • Alzheimer’s disease
  • Aging
  • Functional connectivity