Brain Imaging and Behavior

, Volume 13, Issue 1, pp 255–269 | Cite as

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 LiEmail author
  • Zhijun ZhangEmail author


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.


Apolipoprotein E Episodic memory Alzheimer’s disease Aging Functional connectivity 



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.


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)


  1. Adamson, M. M., Hutchinson, J. B., Shelton, A. L., Wagner, A. D., & Taylor, J. L. (2011). Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE varepsilon4 allele. Neuropsychologia, 49(9), 2448–2455. Scholar
  2. Albers, M. W., Gilmore, G. C., Kaye, J., Murphy, C., Wingfield, A., Bennett, D. A., et al. (2015). At the interface of sensory and motor dysfunctions and Alzheimer’s disease. Alzheimers Dement, 11(1), 70–98. Scholar
  3. Bai, F., Xie, C., Watson, D. R., Shi, Y., Yuan, Y., Wang, Y., et al. (2011). Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study. PLoS ONE, 6(12), e29288. Scholar
  4. Bakkour, A., Morris, J. C., & Dickerson, B. C. (2009). The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology, 72(12), 1048–1055. Scholar
  5. Blumenfeld, R. S., & Ranganath, C. (2007). Prefrontal cortex and long-term memory encoding: an integrative review of findings from neuropsychology and neuroimaging. Neuroscientist, 13(3), 280–291. Scholar
  6. Bondi, M. W., Houston, W. S., Eyler, L. T., & Brown, G. G. (2005). fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology, 64(3), 501–508. Scholar
  7. Buchman, A. S., Boyle, P. A., Wilson, R. S., Beck, T. L., Kelly, J. F., & Bennett, D. A. (2009). Apolipoprotein E e4 allele is associated with more rapid motor decline in older persons. Alzheimer Disease and Associated Disorders, 23(1), 63–69.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Budson, A. E., & Price, B. H. (2005). Memory dysfunction. New England Journal of Medicine, 352(7), 692–699. Scholar
  9. Buracchio, T., Dodge, H. H., Howieson, D., Wasserman, D., & Kaye, J. (2010). The trajectory of gait speed preceding mild cognitive impairment. Archives of Neurology, 67(8), 980–986. Scholar
  10. Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., et al. (2009). Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. New England Journal of Medicine, 361(3), 255–263. Scholar
  11. Chen, G., Chen, G., Xie, C., Ward, B. D., Li, W., Antuono, P., et al. (2012). A method to determine the necessity for global signal regression in resting-state fMRI studies. Magnetic Resonance in Medicine, 68(6), 1828–1835. Scholar
  12. Conejero-Goldberg, C., Gomar, J. J., Bobes-Bascaran, T., Hyde, T. M., Kleinman, J. E., Herman, M. M., et al. (2014). APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Molecular Psychiatry, 19(11), 1243–1250. Scholar
  13. Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C. Jr., et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics, 7(2), 180–184. Scholar
  14. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921–923. Scholar
  15. Dickerson, B. C., Bakkour, A., Salat, D. H., Feczko, E., Pacheco, J., Greve, D. N., et al. (2009). The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cerebral Cortex, 19(3), 497–510. Scholar
  16. Dickerson, B. C., & Eichenbaum, H. (2010). The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology, 35(1), 86–104. Scholar
  17. Dickerson, B. C., Stoub, T. R., Shah, R. C., Sperling, R. A., Killiany, R. J., Albert, M. S., et al. (2011). Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology, 76(16), 1395–1402. Scholar
  18. Dickerson, B. C., & Wolk, D. A., & Alzheimer’s Disease Neuroimaging, I. (2012). MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology, 78(2), 84–90.
  19. Dowell, N. G., Evans, S. L., Tofts, P. S., King, S. L., Tabet, N., & Rusted, J. M. (2016). Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared with non-APOE-e4 carriers. NMR in Biomedicine, 29(5), 614–624. Scholar
  20. Dubois, B., Feldman, H. H., Jacova, C., Cummings, J. L., Dekosky, S. T., Barberger-Gateau, P., et al. (2010). Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurology, 9(11), 1118–1127. Scholar
  21. Edelman, G. M., & Gally, J. A. (2001). Degeneracy and complexity in biological systems. Proceedings of the National Academy of Sciences of the United States of America, 98(24), 13763–13768. Scholar
  22. Etkin, A., Egner, T., & Kalisch, R. (2011). Emotional processing in anterior cingulate and medial prefrontal cortex. Trends in Cognitive Sciences, 15(2), 85–93. Scholar
  23. Fleisher, A. S., Houston, W. S., Eyler, L. T., Frye, S., Jenkins, C., Thal, L. J., et al. (2005). Identification of Alzheimer disease risk by functional magnetic resonance imaging. Archives of Neurology, 62(12), 1881–1888. Scholar
  24. Fox, M. D., & Raichle, M. E. (2007). Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews Neuroscience, 8(9), 700–711. Scholar
  25. Guo, Q., Zhao, Q., Chen, M., Ding, D., & Hong, Z. (2009). A comparison study of mild cognitive impairment with 3 memory tests among Chinese individuals. Alzheimer Disease and Associated Disorders, 23(3), 253–259. Scholar
  26. Han, S. D., Houston, W. S., Jak, A. J., Eyler, L. T., Nagel, B. J., Fleisher, A. S., et al. (2007). Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response. Neurobiology of Aging, 28(2), 238–247. Scholar
  27. Korwek, K. M., Trotter, J. H., Ladu, M. J., Sullivan, P. M., & Weeber, E. J. (2009). ApoE isoform-dependent changes in hippocampal synaptic function. Molecular Neurodegeneration, 4, 21. Scholar
  28. Kukolja, J., Thiel, C. M., Eggermann, T., Zerres, K., & Fink, G. R. (2010). Medial temporal lobe dysfunction during encoding and retrieval of episodic memory in non-demented APOE epsilon4 carriers. Neuroscience, 168(2), 487–497. Scholar
  29. Laske, C., Sohrabi, H. R., Frost, S. M., Lopez-de-Ipina, K., Garrard, P., Buscema, M., et al. (2015). Innovative diagnostic tools for early detection of Alzheimer’s disease. Alzheimers Dement, 11(5), 561–578. Scholar
  30. Maldjian, J. A., Laurienti, P. J., Kraft, R. A., & Burdette, J. H. (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage, 19(3), 1233–1239.PubMedCrossRefGoogle Scholar
  31. Marquis, S., Moore, M. M., Howieson, D. B., Sexton, G., Payami, H., Kaye, J. A., et al. (2002). Independent predictors of cognitive decline in healthy elderly persons. Archives of Neurology, 59(4), 601–606.PubMedCrossRefGoogle Scholar
  32. Mason, P. H., Dominguez, D. J., Winter, B., & Grignolio, A. (2015). Hidden in plain view: degeneracy in complex systems. Biosystems, 128, 1–8. Scholar
  33. McKee, A. C., Au, R., Cabral, H. J., Kowall, N. W., Seshadri, S., Kubilus, C. A., et al. (2006). Visual association pathology in preclinical Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 65(6), 621–630.PubMedCrossRefGoogle Scholar
  34. Melzer, D., Dik, M. G., van Kamp, G. J., Jonker, C., & Deeg, D. J. (2005). The apolipoprotein E e4 polymorphism is strongly associated with poor mobility performance test results but not self-reported limitation in older people. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 60(10), 1319–1323.CrossRefGoogle Scholar
  35. Mielke, M. M., Roberts, R. O., Savica, R., Cha, R., Drubach, D. I., Christianson, T., et al. (2013). Assessing the temporal relationship between cognition and gait: slow gait predicts cognitive decline in the mayo clinic study of aging. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(8), 929–937. Scholar
  36. Modrego, P. J., Fayed, N., & Pina, M. A. (2005). Conversion from mild cognitive impairment to probable Alzheimer’s disease predicted by brain magnetic resonance spectroscopy. The American Journal of Psychiatry, 162(4), 667–675. Scholar
  37. Nadkarni, N. K., Perera, S., Snitz, B. E., Mathis, C. A., Price, J., Williamson, J. D., et al. (2017). Association of brain amyloid-beta with slow gait in elderly individuals without dementia: influence of cognition and apolipoprotein e epsilon4 genotype. JAMA Neurology, 74(1), 82–90. Scholar
  38. Nellessen, N., Rottschy, C., Eickhoff, S. B., Ketteler, S. T., Kuhn, H., Shah, N. J., et al. (2015). Specific and disease stage-dependent episodic memory-related brain activation patterns in Alzheimer’s disease: a coordinate-based meta-analysis. Brain Structure and Function, 220(3), 1555–1571. Scholar
  39. Nichols, L. M., Masdeu, J. C., Mattay, V. S., Kohn, P., Emery, M., Sambataro, F., et al. (2012). Interactive effect of apolipoprotein e genotype and age on hippocampal activation during memory processing in healthy adults. Archives of General Psychiatry, 69(8), 804–813. Scholar
  40. Noppeney, U., Friston, K. J., & Price, C. J. (2004). Degenerate neuronal systems sustaining cognitive functions. Journal of Anatomy, 205(6), 433–442. Scholar
  41. Park, H. J., & Friston, K. (2013). Structural and functional brain networks: from connections to cognition. Science, 342(6158), 1238411. Scholar
  42. Pergola, G., & Suchan, B. (2013). Associative learning beyond the medial temporal lobe: many actors on the memory stage. Frontiers in Behavioral Neuroscience, 7, 162. Scholar
  43. Putcha, D., Brickhouse, M., O’Keefe, K., Sullivan, C., Rentz, D., Marshall, G., et al. (2011). Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in non-demented elderly adults. Journal of Neuroscience, 31(48), 17680–17688. Scholar
  44. Rigoux, L., & Daunizeau, J. (2015). Dynamic causal modelling of brain-behaviour relationships. NeuroImage, 117, 202–221. Scholar
  45. Rosenberg, M. D., Finn, E. S., Scheinost, D., Papademetris, X., Shen, X., Constable, R. T., et al. (2016). A neuromarker of sustained attention from whole-brain functional connectivity. Nature Neuroscience, 19(1), 165–171. Scholar
  46. Samieri, C., Proust-Lima, C., Glymour, M. M., Okereke, O. I., Amariglio, R. E., Sperling, R. A., et al (2014). Subjective cognitive concerns, episodic memory, and the APOE epsilon4 allele. Alzheimers Dement, 10(6), 752–759 e751. Scholar
  47. Sanchez, P. E., Zhu, L., Verret, L., Vossel, K. A., Orr, A. G., Cirrito, J. R., et al. (2012). Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proceedings of the National Academy of Sciences of the United States of America, 109(42), E2895–2903. Scholar
  48. Shu, H., Shi, Y., Chen, G., Wang, Z., Liu, D., Yue, C., et al. (2016). Opposite neural trajectories of apolipoprotein e 4 and 2 alleles with aging associated with different risks of Alzheimer’s disease. Cerebral Cortex, 26(4), 1421–1429. Scholar
  49. Sperling, R. A., Dickerson, B. C., Pihlajamaki, M., Vannini, P., LaViolette, P. S., Vitolo, O. V., et al. (2010). Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Medicine, 12(1), 27–43. Scholar
  50. Suri, S., Heise, V., Trachtenberg, A. J., & Mackay, C. E. (2013). The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE varepsilon2. Neuroscience and Biobehavioral Reviews, 37(10 Pt 2), 2878–2886. Scholar
  51. Suthana, N. A., Krupa, A., Donix, M., Burggren, A., Ekstrom, A. D., Jones, M., et al. (2010). Reduced hippocampal CA2, CA3, and dentate gyrus activity in asymptomatic people at genetic risk for Alzheimer’s disease. NeuroImage, 53(3), 1077–1084. Scholar
  52. Touroutoglou, A., Andreano, J. M., Barrett, L. F., & Dickerson, B. C. (2015). Brain network connectivity-behavioral relationships exhibit trait-like properties: Evidence from hippocampal connectivity and memory. Hippocampus, 25(12), 1591–1598. Scholar
  53. Trachtenberg, A. J., Filippini, N., & Mackay, C. E. (2012). The effects of APOE-epsilon4 on the BOLD response. Neurobiology of Aging, 33(2), 323–334. Scholar
  54. Tulving, E., & Markowitsch, H. J. (1998). Episodic and declarative memory: role of the hippocampus. Hippocampus, 8(3), 198–204.<198::AID-HIPO2>3.0.CO;2-G.PubMedCrossRefGoogle Scholar
  55. Tuminello, E. R., & Han, S. D. (2011). The apolipoprotein e antagonistic pleiotropy hypothesis: review and recommendations. International Journal of Alzheimer’s Disease, 2011, 726197. Scholar
  56. Valdes-Sosa, P. A., Roebroeck, A., Daunizeau, J., & Friston, K. (2011). Effective connectivity: influence, causality and biophysical modeling. NeuroImage, 58(2), 339–361. Scholar
  57. Verghese, J., Wang, C., Lipton, R. B., Holtzer, R., & Xue, X. (2007). Quantitative gait dysfunction and risk of cognitive decline and dementia. Journal of Neurology, Neurosurgery and Psychiatry, 78(9), 929–935. Scholar
  58. Vertes, R. P., Albo, Z., & Viana Di Prisco, G. (2001). Theta-rhythmically firing neurons in the anterior thalamus: implications for mnemonic functions of Papez’s circuit. Neuroscience, 104(3), 619–625. Scholar
  59. Vincent, J. L., Snyder, A. Z., Fox, M. D., Shannon, B. J., Andrews, J. R., Raichle, M. E., et al. (2006). Coherent spontaneous activity identifies a hippocampal-parietal memory network. Journal of Neurophysiology, 96(6), 3517–3531. Scholar
  60. Westlye, E. T., Lundervold, A., Rootwelt, H., Lundervold, A. J., & Westlye, L. T. (2011). Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE epsilon4 carriers: relationships with memory performance. Journal of Neuroscience, 31(21), 7775–7783. Scholar
  61. Wilson, R. S., Bienias, J. L., Berry-Kravis, E., Evans, D. A., & Bennett, D. A. (2002). The apolipoprotein E epsilon 2 allele and decline in episodic memory. Journal of Neurology, Neurosurgery and Psychiatry, 73(6), 672–677.PubMedCrossRefGoogle Scholar
  62. Yokoyama, J. S., Lee, A. K., Takada, L. T., Busovaca, E., Bonham, L. W., Chao, S. Z., et al. (2015). Apolipoprotein epsilon4 is associated with lower brain volume in cognitively normal Chinese but not white older adults. PLoS ONE, 10(3), e0118338. Scholar

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
    Email author
  • Zhijun Zhang
    • 1
    Email author
  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

Personalised recommendations