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Disrupted Brain Structural Connectivity: Pathological Interactions Between Genetic APOE ε4 Status and Developed MCI Condition

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Abstract

The ε4 allele of the apolipoprotein E (APOE) gene and mild cognitive impairment (MCI) are both risk factors for Alzheimer’s disease (AD). One factor is genetic, and the other is a developed condition during the aging process. The current study intended to discover the interactions of these two factors, which may be useful in the construction of a sensitive biomarker for early identification and intervention. Eight hundred eighty-five Chinese Han ethnic subjects (aged 55 and older) completed neuropsychological tests and APOE genotyping. One hundred ten of these participants underwent magnetic resonance imaging (MRI) for T1 structural and diffusion tensor imaging scans. Subjects were divided into four groups according to APOE ε4 carrying status and MCI condition: ε4+ MCI, ε4+ normal cognition (NC), ε4− MCI, and ε4− NC. In the studied Han population in Beijing, 16.9 % (ε2ε4 = 1.1 %, ε3ε4 = 14.8 %, and ε4ε4 = 0.9 %) carried at least one ε4 allele. Significant interactions between APOE ε4 and MCI were found in general cognitive function (p = 0.001) and white matter connectivity network (clustering coefficient, p = 0.004, and local efficiency, p = 0.011); the combination of ε4 positivity and MCI was accompanied by reductions in Mini-Mental Status Examination (MMSE) scores, global white matter network connectivity, and the right hippocampus (rHIP) nodal efficiency within that network (false discovery rate (FDR), p < 0.05). Our results suggest the presence of a genetic risk and MCI led to more severe pathological symptoms and could be informative in the implementation of clinical trials for early stages of AD.

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References

  1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL 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

    Article  CAS  PubMed  Google Scholar 

  2. Frisoni GB, Govoni S, Geroldi C, Bianchetti A, Calabresi L, Franceschini G, Trabucchi M (1995) Gene dose of the epsilon 4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer’s disease. Ann Neurol 37(5):596–604. doi:10.1002/ana.410370509

    Article  CAS  PubMed  Google Scholar 

  3. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the Journal of the American Medical Association 278(16):1349–1356

    Article  CAS  PubMed  Google Scholar 

  4. Maloney B, Ge YW, Petersen RC, Hardy J, Rogers JT, Perez-Tur J, Lahiri DK (2010) Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet 153B(1):185–201. doi:10.1002/ajmg.b.30973

    CAS  PubMed  Google Scholar 

  5. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H et al (2006) Mild cognitive impairment. Lancet 367(9518):1262–1270. doi:10.1016/S0140-6736(06)68542-5

    Article  PubMed  Google Scholar 

  6. Hashimoto M, Yasuda M, Tanimukai S, Matsui M, Hirono N, Kazui H, Mori E (2001) Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer’s disease. Neurology 57(8):1461–1466

    Article  CAS  PubMed  Google Scholar 

  7. Geroldi C, Pihlajamaki M, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M et al (1999) APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 53(8):1825–1832

    Article  CAS  PubMed  Google Scholar 

  8. Persson J, Lind J, Larsson A, Ingvar M, Cruts M, Van Broeckhoven C, Adolfsson R, Nilsson LG et al (2006) Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD? Neurology 66(7):1029–1033. doi:10.1212/01.wnl.0000204180.25361.48

    Article  CAS  PubMed  Google Scholar 

  9. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J (2005) Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A 102(23):8299–8302. doi:10.1073/pnas.0500579102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL et al (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). NeuroImage 45(4):1107–1116. doi:10.1016/j.neuroimage.2008.12.072

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brown JA, Terashima KH, Burggren AC, Ercoli LM, Miller KJ, Small GW, Bookheimer SY (2011) Brain network local interconnectivity loss in aging APOE-4 allele carriers. Proc Natl Acad Sci U S A 108(51):20760–20765. doi:10.1073/pnas.1109038108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Putcha D, Brickhouse M, O’Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R (2011) Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in non-demented elderly adults. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 31(48):17680–17688. doi:10.1523/JNEUROSCI.4740-11.2011

    Article  CAS  Google Scholar 

  13. Bondi MW, Salmon DP, Monsch AU, Galasko D, Butters N, Klauber MR, Thal LJ, Saitoh T (1995) Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults. Neurology 45(12):2203–2206

    Article  CAS  PubMed  Google Scholar 

  14. Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10(5):333–344. doi:10.1038/nrn2620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 101(13):4637–4642. doi:10.1073/pnas.0308627101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Westlye LT, Reinvang I, Rootwelt H, Espeseth T (2012) Effects of APOE on brain white matter microstructure in healthy adults. Neurology 79(19):1961–1969. doi:10.1212/WNL.0b013e3182735c9c

    Article  CAS  PubMed  Google Scholar 

  17. Li X, Ma C, Zhang J, Liang Y, Chen Y, Chen K, Wang J, Zhang Z et al (2013) Prevalence of and potential risk factors for mild cognitive impairment in community-dwelling residents of Beijing. J Am Geriatr Soc 61(12):2111–2119

    Article  PubMed  Google Scholar 

  18. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56(3):303–308

    Article  CAS  PubMed  Google Scholar 

  19. Shu N, Liang Y, Li H, Zhang J, Li X, Wang L, He Y, Wang Y et al (2012) Disrupted topological organization in white matter structural networks in amnestic mild cognitive impairment: relationship to subtype. Radiology 265(2):518–527. doi:10.1148/radiol.12112361

    Article  PubMed  Google Scholar 

  20. Cui Z, Zhong S, Xu P, He Y, Gong G (2013) PANDA: a pipeline toolbox for analyzing brain diffusion images. Front Hum Neurosci 7:42. doi:10.3389/fnhum.2013.00042

    PubMed  PubMed Central  Google Scholar 

  21. Rubinov M, Sporns O (2010) Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52(3):1059–1069

    Article  PubMed  Google Scholar 

  22. Achard S, Bullmore E (2007) Efficiency and cost of economical brain functional networks. PLoS Comput Biol 3(2):e17

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xia M, Wang J, He Y (2013) BrainNet Viewer: a network visualization tool for human brain connectomics. PLoS One 8(7):e68910. doi:10.1371/journal.pone.0068910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nilsson LG, Adolfsson R, Backman L, Cruts M, Nyberg L, Small BJ, Van Broeckoven C (2006) The influence of APOE status on episodic and semantic memory: data from a population-based study. Neuropsychology 20(6):645–657. doi:10.1037/0894-4105.20.6.645

    Article  PubMed  Google Scholar 

  25. Dik MG, Jonker C, Comijs HC, Bouter LM, Twisk JW, van Kamp GJ, Deeg DJ (2001) Memory complaints and APOE-epsilon4 accelerate cognitive decline in cognitively normal elderly. Neurology 57(12):2217–2222

    Article  CAS  PubMed  Google Scholar 

  26. Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG (2004) Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology 62(11):1990–1995

    Article  CAS  PubMed  Google Scholar 

  27. Drzezga A, Grimmer T, Riemenschneider M, Lautenschlager N, Siebner H, Alexopoulus P, Minoshima S, Schwaiger M et al (2005) Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. J Nucl Med 46(10):1625–1632

    CAS  PubMed  Google Scholar 

  28. Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, Thompson PM, Jack CR Jr et al (2009) MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain 132(Pt 4):1067–1077. doi:10.1093/brain/awp007

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM, Trojanowski JQ, Aisen PS, Weiner M et al (2010) Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann Neurol 67(3):308–316. doi:10.1002/ana.21953

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Masters CL, Beyreuther K (2006) Alzheimer’s centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain: A Journal of Neurology 129(Pt 11):2823–2839. doi:10.1093/brain/awl251

    Article  Google Scholar 

  31. Mikos AE, Piryatinsky I, Tremont G, Malloy PF (2013) The APOE epsilon4 allele is associated with increased frontally mediated neurobehavioral symptoms in amnestic MCI. Alzheimer Dis Assoc Disord 27(2):109–115. doi:10.1097/WAD.0b013e318266c6c3

    Article  PubMed  Google Scholar 

  32. Dik MG, Jonker C, Bouter LM, Geerlings MI, van Kamp GJ, Deeg DJ (2000) APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology 54(7):1492–1497

    Article  CAS  PubMed  Google Scholar 

  33. Bunce D, Fratiglioni L, Small BJ, Winblad B, Backman L (2004) APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 63(5):816–821

    Article  CAS  PubMed  Google Scholar 

  34. Ishioka YL, Gondo Y, Fuku N, Inagaki H, Masui Y, Takayama M, Abe Y, Arai Y et al (2016) Effects of the APOE epsilon4 allele and education on cognitive function in Japanese centenarians. Age (Dordr). doi:10.1007/s11357-016-9944-8

    Google Scholar 

  35. Bullmore E, Sporns O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 10(3):186–198. doi:10.1038/nrn2575

    Article  CAS  PubMed  Google Scholar 

  36. He Y, Chen Z, Evans A (2008) Structural insights into aberrant topological patterns of large-scale cortical networks in Alzheimer’s disease. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28(18):4756–4766. doi:10.1523/JNEUROSCI.0141-08.2008

    Article  CAS  Google Scholar 

  37. Wee CY, Yap PT, Zhang D, Denny K, Browndyke JN, Potter GG, Welsh-Bohmer KA, Wang L et al (2012) Identification of MCI individuals using structural and functional connectivity networks. NeuroImage 59(3):2045–2056. doi:10.1016/j.neuroimage.2011.10.015

    Article  PubMed  Google Scholar 

  38. Greicius MD, Krasnow B, Reiss AL, Menon V (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A 100(1):253–258. doi:10.1073/pnas.0135058100

    Article  CAS  PubMed  Google Scholar 

  39. Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P (2005) Altered resting state networks in mild cognitive impairment and mild Alzheimer’s disease: an fMRI study. Hum Brain Mapp 26(4):231–239. doi:10.1002/hbm.20160

    Article  PubMed  Google Scholar 

  40. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D’Angelo G, Liu C, Dixit S et al (2010) APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Abeta42. J Neurosci 30(50):17035–17040. doi:10.1523/JNEUROSCI.3987-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qi Z, Wu X, Wang Z, Zhang N, Dong H, Yao L, Li K (2010) Impairment and compensation coexist in amnestic MCI default mode network. NeuroImage 50(1):48–55. doi:10.1016/j.neuroimage.2009.12.025S1053-8119(09)01313-5

    Article  PubMed  Google Scholar 

  42. Risacher SL, Kim S, Shen L, Nho K, Foroud T, Green RC, Petersen RC, Jack CR Jr et al (2013) The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI). Front Aging Neurosci 5:11. doi:10.3389/fnagi.2013.00011

    Article  PubMed  PubMed Central  Google Scholar 

  43. Han SD, Houston WS, Jak AJ, Eyler LT, Nagel BJ, Fleisher AS, Brown GG, Corey-Bloom J et al (2007) Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response. Neurobiol Aging 28(2):238–247. doi:10.1016/j.neurobiolaging.2005.12.013

    Article  CAS  PubMed  Google Scholar 

  44. Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, DePeau K, Rentz DM et al (2006) Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci 26(40):10222–10231. doi:10.1523/JNEUROSCI.2250-06.2006

    Article  CAS  PubMed  Google Scholar 

  45. Han SD, Bondi MW (2008) Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimers Dement 4(4):251–254. doi:10.1016/j.jalz.2008.02.006

    Article  CAS  PubMed  Google Scholar 

  46. Bondi MW, Houston WS, Eyler LT, Brown GG (2005) fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology 64(3):501–508. doi:10.1212/01.WNL.0000150885.00929.7E

    Article  PubMed  PubMed Central  Google Scholar 

  47. Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF et al (2009) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 106(17):7209–7214. doi:10.1073/pnas.08118791060811879106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C et al (2007) Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cereb Cortex 17(8):1934–1947. doi:10.1093/cercor/bhl103

    Article  PubMed  Google Scholar 

  49. van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci 10(4):272–282. doi:10.1038/nrn2614

    Article  PubMed  Google Scholar 

  50. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 32(26):8767–8777. doi:10.1523/JNEUROSCI.0615-12.2012

    Article  CAS  Google Scholar 

  51. Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW (2012) Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73(6):1216–1227. doi:10.1016/j.neuron.2012.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Raj A, Kuceyeski A, Weiner M (2012) A network diffusion model of disease progression in dementia. Neuron 73(6):1204–1215. doi:10.1016/j.neuron.2011.12.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344(8925):769–772

    Article  CAS  PubMed  Google Scholar 

  54. Honea RA, Vidoni E, Harsha A, Burns JM (2009) Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J Alzheimers Dis 18(3):553–564. doi:10.3233/JAD-2009-1163G6559086962225K7

    Article  PubMed  PubMed Central  Google Scholar 

  55. Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, Rusinek H, Pelton GH et al (2007) Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology 68(11):828–836. doi:10.1212/01.wnl.0000256697.20968.d7

    Article  CAS  PubMed  Google Scholar 

  56. Latora V, Marchiori M (2001) Efficient behavior of small-world networks. Phys Rev Lett 87(19):198701

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Financial support for this study was provided by State Key Program of National Natural Science Foundation of China 81430100; by National Natural Science Foundation of China 81274001; by Beijing Municipal Science & Technology Commission Z161100000216135.

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Authors and Affiliations

  1. State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, No. 19 Xinjiekouwai Street, Beijing, 100875, China

    Chao Ma, Jun Wang, Junying Zhang, Xin Li, Ni Shu, Yaojing Chen, Zhen Liu & Zhanjun Zhang

  2. BABRI Centre, Beijing Normal University, Beijing, 100875, People’s Republic of China

    Chao Ma, Jun Wang, Junying Zhang, Kewei Chen, Xin Li, Ni Shu, Yaojing Chen, Zhen Liu & Zhanjun Zhang

  3. Banner Alzheimer’s Institute, Phoenix, AZ, 85006, USA

    Kewei Chen

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  1. Chao Ma
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Ma, C., Wang, J., Zhang, J. et al. Disrupted Brain Structural Connectivity: Pathological Interactions Between Genetic APOE ε4 Status and Developed MCI Condition. Mol Neurobiol 54, 6999–7007 (2017). https://doi.org/10.1007/s12035-016-0224-5

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