Disrupted Brain Structural Connectivity: Pathological Interactions Between Genetic APOE ε4 Status and Developed MCI Condition
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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Limited evidence suggests that APOE4 may drive accelerated hippocampal atrophy and network disruption with MCI, though others report no modifying effect of APOE4 on WM microstructure in MCI.
“limited evidence suggests that APOE4 may drive accelerated hippocampal atrophy and network disruption with MCI [22], though others report no modifying effect of APOE4 on WM microstructure in MCI [23].”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [22]
Cites
Complex brain networks: graph theoretical analysis of structural and functional systems
Bullmore, E., & Sporns, O. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2575 · Cited by 11,820 · see citing works
Complex network measures of brain connectivity: Uses and interpretations
Rubinov, M., & Sporns, O. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2009.10.003 · Cited by 11,522 · see citing works
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Mild Cognitive Impairment: Clinical Characterization and Outcome
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999) · Archives of Neurology · doi:10.1001/archneur.56.3.303 · Cited by 8,980 · see citing works
Functional connectivity in the resting brain: a network analysis of the default mode hypothesis
Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0135058100 · Cited by 6,358 · see citing works
Efficient behavior of small-world networks
Latora, V., & Marchiori, M. (2001) · Physical Review Letters · doi:10.1103/physrevlett.87.198701 · Cited by 5,119 · see citing works
BrainNet Viewer: A Network Visualization Tool for Human Brain Connectomics
Xia, M., Wang, J., & He, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068910 · Cited by 4,106 · see citing works
Self-citationGauthier, S. G., Reisberg, ., Zaudig, M., Petersen, R. C., Ritchie, K. A., Broich, K., Belleville, S., Brodaty, H., Bennett, D. A., Chertkow, H. M., et al. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68542-5 · Cited by 3,920 · see citing works
Greicius, M. D., Srivastava, G., Reiss, A. L., & Menon, V. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308627101 · Cited by 3,684 · see citing works
Efficiency and Cost of Economical Brain Functional Networks
Achard, S., & Bullmore, E. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030017 · Cited by 2,553 · see citing works
Distinct patterns of brain activity in young carriers of the <i>APOE</i> -ε4 allele
Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., Matthews, P. M., Beckmann, C. F., & Mackay, C. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811879106 · Cited by 1,613 · see citing works
Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
West, M. J., Coleman, P. D., Flood, D. G., & Troncoso, J. C. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92338-8 · Cited by 1,267 · cited 1× · see citing works
“Hippocampal volume loss is an indicator of AD pathology [53] and is accelerated by the presence of ε4 [28].”
BackgroundApolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network
van Strien, N. M., Cappaert, N. L. M., & Witter, M. P. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2614 · Cited by 1,041 · see citing works
He, Y., Chen, Z., & Evans, A. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0141-08.2008 · Cited by 965 · see citing works
PANDA: a pipeline toolbox for analyzing brain diffusion images
Cui, Z., Zhong, S., Xu, P., Yong He, A., & Gong, G. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00042 · Cited by 758 · see citing works
Hippocampal and entorhinal atrophy in mild cognitive impairment
Devanand, D. P., Pradhaban, G., Liu, X., Khandji, A., Santi, S. D., Segal, S., Rusinek, H., Pelton, G. H., Honig, L. S., Mayeux, R. P., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000256697.20968.d7 · Cited by 739 · see citing works
Rombouts, S. A. R. B., Barkhof, F., Goekoop, R., Stam, C. J., & Scheltens, P. (2005) · Human Brain Mapping · doi:10.1002/hbm.20160 · Cited by 734 · see citing works
Celone, K., Calhoun, V. D., Dickerson, B. C., Atri, A., Chua, E. F., Miller, S. L., DePeau, K. M., Rentz, D., Selkoe, D. J., Blacker, D., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2250-06.2006 · Cited by 733 · see citing works
A network diffusion model of disease progression in dementia
Raj, A., Kuceyeski, A., & Weiner, M. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.040 · Cited by 723 · see citing works
Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome
Zhou, J., Gennatas, E. D., Kramer, J. H., Miller, B. L., & Seeley, W. W. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.004 · Cited by 706 · see citing works
Schuff, N., Woerner, N., Boreta, L., Kornfield, T., Shaw, L. M., Trojanowski, J. Q., Thompson, P. M., Jack, C. R., Weiner, M. W., & Initiative, T. A. D. N. (2008) · Brain · doi:10.1093/brain/awp007 · Cited by 679 · see citing works
Sheline, Y. I., Morris, J. C., Snyder, A. Z., Price, J. L., Yan, Z., D’Angelo, G., Liu, C., Dixit, S., Benzinger, T. L. S., Fagan, A. M., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3987-10.2010 · Cited by 430 · see citing works
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500579102 · Cited by 401 · see citing works
Self-citationIdentification of MCI individuals using structural and functional connectivity networks
Chong-yaw Wee, A., Yap, P., Zhang, D., Denny, K., Browndyke, J. N., Potter, G. G., Welsh-Bohmer, K. A., Wang, L., & Shen, D. G. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.10.015 · Cited by 378 · see citing works
fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease
Bondi, M. W., Houston, W. S., Eyler, L. T., & Brown, G. G. (2005) · Neurology · doi:10.1212/01.wnl.0000150885.00929.7e · Cited by 372 · see citing works
Impairment and compensation coexist in amnestic MCI default mode network
Qi, Z., Wu, X., Wang, Z., Zhang, N., Dong, H., Yao, L., & Li, K. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.12.025 · Cited by 323 · see citing works
Langbaum, J. B. S., Chen, K., Lee, W., Reschke, C., Bandy, D., Fleisher, A. S., Alexander, G. E., Foster, N. L., Weiner, M. W., Koeppe, R. A., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2008.12.072 · Cited by 279 · see citing works
Self-citationPrediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET.
Drzezga, A. E., Grimmer, T., Riemenschneider, M., Lautenschlager, N. T., Siebner, H. R., Alexopoulus, P., Minoshima, S., Schwaiger, M., & Kurz, A. (2005) · PubMed · Cited by 277 · see citing works
Better Memory and Neural Efficiency in Young Apolipoprotein E 4 Carriers
Mondadori, C. R. A., de Quervain, D. J. ‐., Buchmann, A., Mustovic, H., Wollmer, M. A., Schmidt, C. F., Boesiger, P., Hock, C., Nitsch, R. M., Papassotiropoulos, A., et al. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhl103 · Cited by 265 · see citing works
Putcha, D., Brickhouse, M. J., O’Keefe, K., Sullivan, C., Rentz, D. M., Marshall, G. A., Dickerson, B. C., & Sperling, R. A. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4740-11.2011 · Cited by 258 · see citing works
Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid
Nath, S., Agholme, L., Kurudenkandy, F. R., Granseth, B., Marcusson, J., & Hallbeck, M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0615-12.2012 · Cited by 244 · see citing works
Episodic memory changes are associated with the APOE- epsilon 4 allele in nondemented older adults
Bondi, M. W., Salmon, D. P., Monsch, A. U., Galasko, D., Butters, N., Klauber, M. R., Thal, L. J., & Saitoh, T. (1995) · Neurology · doi:10.1212/wnl.45.12.2203 · Cited by 236 · see citing works
Memory complaints and APOE-ε4 accelerate cognitive decline in cognitively normal elderly
Dik, M. G., Jonker, C., Comijs, H. C., Bouter, L. M., Twisk, J. W. R., van Kamp, G. J., & Deeg, D. J. H. (2001) · Neurology · doi:10.1212/wnl.57.12.2217 · Cited by 233 · see citing works
Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele
Caselli, R. J., Reiman, E. M., Osborne, D., Hentz, J. G., Baxter, L. C., Hernandez, J. L., & Alexander, G. (2004) · Neurology · doi:10.1212/01.wnl.0000129533.26544.bf · Cited by 231 · see citing works
Impact of APOE on the Healthy Aging Brain: A Voxel-Based MRI and DTI Study
Honea, R. A., Vidoni, E. D., Harsha, A., & Burns, J. M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1163 · Cited by 222 · see citing works
Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease
Vemuri, P., Wiste, H. J., Weigand, S. D., Knopman, D. S., Shaw, L. M., Trojanowski, J. Q., Aisen, P. S., Weiner, M., Petersen, R. C., Jack, C. R., et al. (2010) · Annals of Neurology · doi:10.1002/ana.21953 · Cited by 195 · see citing works
Brain network local interconnectivity loss in aging APOE -4 allele carriers
Brown, J. A., Terashima, K. H., Burggren, A. C., Ercoli, L. M., Miller, K. J., Small, G. W., & Bookheimer, S. Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109038108 · Cited by 167 · see citing works
Altered brain white matter integrity in healthy carriers of the APOE ε4 allele
Persson, J., Lind, J., Larsson, A., Ingvar, M., Cruts, M., Broeckhoven, C. V., Adolfsson, R., Nilsson, L. G., & Nyberg, L. H. (2006) · Neurology · doi:10.1212/01.wnl.0000204180.25361.48 · Cited by 161 · see citing works
APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD
Geroldi, C., Pihlajamaki, M. M., Laakso, M. P., DeCarli, C. S., Beltramello, A., Bianchetti, A., Soininen, H. S., Trabucchi, M., & Frisoni, G. B. (1999) · Neurology · doi:10.1212/wnl.53.8.1825 · Cited by 155 · see citing works
(2011) · Routledge eBooks · doi:10.4324/9780203152836-7 · Cited by 154 · see citing works
Han, S. D., Houston, W. S., Jak, A. J., Eyler, L. T., Nagel, B. J., Fleisher, A., Brown, G. G., Corey‐Bloom, J., Salmon, D. P., Thal, L. J., et al. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.12.013 · Cited by 151 · see citing works
Frisoni, G. B., Govoni, S., Geroldi, C., Bianchetti, A., Calabresi, L., Franceschini, G., & Trabucchi, M. (1995) · Annals of Neurology · doi:10.1002/ana.410370509 · Cited by 149 · see citing works
Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis
Han, S. D., & Bondi, M. W. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.02.006 · Cited by 146 · see citing works
Apolipoprotein E ε4 and the pattern of regional brain atrophy in Alzheimer’s disease
Hashimoto, M., Yasuda, M., Tanimukai, S., Matsui, M., Hirono, N., Kazui, H., & Mori, E. (2001) · Neurology · doi:10.1212/wnl.57.8.1461 · Cited by 143 · see citing works
The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)
Risacher, S. L. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00011 · Cited by 143 · see citing works
Masters, C. L., & Beyreuther, K. (2006) · Brain · doi:10.1093/brain/awl251 · Cited by 143 · see citing works
The influence of apoe status on episodic and semantic memory: Data from a population-based study.
Nilsson, L., Adolfsson, R., Bäckman, L., Cruts, M., Nyberg, L. H., Small, B. J., & Broeckhoven, C. V. (2006) · Neuropsychology · doi:10.1037/0894-4105.20.6.645 · Cited by 132 · see citing works
APOE-ε4 is associated with memory decline in cognitively impaired elderly
Dik, M. G., Jonker, C., Bouter, L. M., Geerlings, M. I., van Kamp, G. J., & Deeg, D. J. H. (2000) · Neurology · doi:10.1212/wnl.54.7.1492 · Cited by 126 · see citing works
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · see citing works
Shu, N., Liang, Y., Li, H., Zhang, J., Li, X., Wang, L. Y., Yong He, A., Wang, Y., & Zhang, Z. (2012) · Radiology · doi:10.1148/radiol.12112361 · Cited by 122 · see citing works
Self-citationAPOE and cognitive decline in preclinical Alzheimer disease and non-demented aging
Bunce, D. J., Fratiglioni, L., Small, B. J., Winblad, B. G., & Bäckman, L. (2004) · Neurology · doi:10.1212/01.wnl.0000137041.86153.42 · Cited by 111 · see citing works
Li, X., Ma, C., Zhang, J., Liang, Y., Chen, Y., Chen, K., Wang, J., Zhang, Z., & Wang, Y. (2013) · Journal of the American Geriatrics Society · doi:10.1111/jgs.12552 · Cited by 102 · see citing works
Self-citationEffects of <i>APOE</i> on brain white matter microstructure in healthy adults
Westlye, L. T., Reinvang, I., Rootwelt, H., & Espeseth, T. (2012) · Neurology · doi:10.1212/wnl.0b013e3182735c9c · Cited by 84 · see citing works
Maloney, B., Ge, Y., Petersen, R. C., Hardy, J., Rogers, J. T., Pérez‐Tur, J., & Lahiri, D. K. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30973 · Cited by 44 · see citing works
Effects of the APOE ε4 allele and education on cognitive function in Japanese centenarians
Ishioka, Y., Gondo, Y., Fuku, N., Inagaki, H., Masui, Y., Takayama, M., Abe, Y., Arai, Y., & Hirose, N. (2016) · AGE · doi:10.1007/s11357-016-9944-8 · Cited by 20 · see citing works
Mikos, A. E., Piryatinsky, I., Tremont, G. N., & Malloy, P. F. (2012) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318266c6c3 · Cited by 5 · see citing works
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The human connectome in Alzheimer disease — relationship to biomarkers and genetics
Yu, M., Sporns, O., & Saykin, A. J. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00529-1 · Cited by 265 · see citing works
Reas, E. T., Triebswetter, C., Banks, S. J., & McEvoy, L. K. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-023-01380-w · Cited by 20 · see citing works
“…diffusion MRI studies have focused on cognitively normal individuals or those with AD dementia, limited evidence suggests that APOE4 may drive accelerated hippocampal atrophy and network disruption with MCI [22], though others report no modifying effect of APOE4 on WM microstructure in MCI [23].”
Background
- Authors
- Ma, C., Wang, J., Zhang, J., Chen, K., Li, X., Shu, N., Chen, Y., Liu, Z., & Zhang, Z.
- Affiliations
- Beijing Normal University (CN)
- Corresponding author
- Zhang, Zhanjun
- Venue
- Molecular Neurobiology
- Published
- 2016-10-26
- Volume
- 54
- Issue
- 9
- Pages
- 6999-7007
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2540828910
- Cited by
- 21
- References
- 57
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 5 · 2018: 2
- FWCI
- 0.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- APOE ε4, mild cognitive impairment, Alzheimer's disease, structural brain connectivity, white matter networks, hippocampus, genetic risk, gene-environment interaction, diffusion tensor imaging, clustering coefficient, local efficiency, Han Chinese
- MeSH terms
- Aged, Brain, Female, Hippocampus, Humans, Male, Nerve Net, Neuropsychological Tests, Apolipoprotein E4, Cognitive Dysfunction, White Matter
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