Cortical Thickness and Microstructural White Matter Changes Detect Amnestic Mild Cognitive Impairment
Abstract
Both the apolipoprotein E (APOE) ɛ4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer’s disease (AD). The primary aim of this study was to determine whether the aMCI-related abnormality in gray matter (GM) cortical thickness and white matter (WM) tracts integrity would be modified by the APOE genotype. A total of 146 older adults, including 64 aMCI patients (28 ɛ4 carriers and 36 non-carriers) and 82 healthy controls (39 ɛ4 carriers and 43 non-carriers), underwent a standardized clinical interview, neuropsychological battery assessment, and multi-modal brain magnetic resonance imaging scans. Compared with control subjects, the patients with aMCI showed significantly reduced cortical thickness bilaterally in the parahippocampal gyrus and disrupted WM integrity in the limbic tracts (e.g., increased mean diffusivity in the right parahippocampal cingulum and bilateral uncinate fasciculus). However, no significant main effects of the APOE genotype and diagnosis-by-genotype interaction on GM thickness and WM integrity were observed. Further, diffusivity measures of the limbic WM tracts were significantly correlated with the parahippocampal atrophy in aMCI. Importantly, the parahippocampal thickness and diffusivity measures of the limbic WM tracts were significantly correlated with the cognitive performance (i.e., episodic memory Z score) in patients with aMCI. These results demonstrate that WM microstructural disruptions in the limbic tracts are present at the early stage of AD in an APOE-independent manner; and this degeneration may occur progressively, in parallel with parahippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.
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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 [23]
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The cingulum bundle: Anatomy, function, and dysfunction
Bubb, E. J., Metzler-Baddeley, C., & Aggleton, J. P. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.05.008 · Cited by 740 · see citing works
“Furthermore, and in contrast to MCI studies without FWE correction (see Yu et al., 2017), Metzler-Baddeley et al. (2012a, b) did not find any FA reductions or increases in MD, but rather observed a trend for increased FA in left and right parahippocampal cinguli in MCI.”
InfluentialYu, J., Lam, C. L. M., & Lee, T. M. C. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.10.026 · Cited by 81 · see citing works
Zheng, W., Yao, Z., Xie, Y., Fan, J., & Hu, B. (2018) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2018.06.004 · Cited by 59 · see citing works
The cingulum as a marker of individual differences in neurocognitive development
Bathelt, J., Johnson, A., Zhang, M., Astle, D. E., & Astle, D. E. (2019) · Scientific Reports · doi:10.1038/s41598-019-38894-z · Cited by 42 · see citing works
Liu, W., Liu, L., Cheng, X., Ge, H., Hu, G., Xue, C., Qi, W., Xu, W., Chen, S., Gao, R., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.710172 · Cited by 35 · see citing works
Zhu, L., Wang, Z., Du, Z. J., Qi, X., Shu, H., Liu, D., Su, F., Ye, Q., Liu, X., Zhou, Z., et al. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00498-3 · Cited by 30 · see citing works
Self-citationLi, X., Xia, J., Ma, C., Chen, K., Xu, K., Zhang, J., Chen, Y., Li, H., Wei, D., & Zhang, Z. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz090 · Cited by 27 · see citing works
Self-citationJiang, H., He, N., Sun, Y., Jian, F., Bian, L., Shen, J.-K., Yan, F., Pan, S., & Sun, Q. (2017) · Brain Research · doi:10.1016/j.brainres.2017.04.007 · Cited by 23 · see citing works
Chakraborty, S., Ouhaz, Z., Mason, S. A., & Mitchell, A. S. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14078 · Cited by 23 · see citing works
Sherbaf, F. G., Mohajer, B., Ashraf‐Ganjouei, A., Zadeh, M. M., Javinani, A., Moghaddam, H. S., Shandiz, M. S., & Aarabi, M. H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00608 · Cited by 21 · 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].”
BackgroundZhu, L., Shu, H., Liu, D., Guo, Q., Wang, Z., & Zhang, Z. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00289 · Cited by 17 · see citing works
Self-citationPelekanos, V., Premereur, E., Mitchell, D. J., Chakraborty, S., Mason, S., Lee, A. C. H., & Mitchell, A. S. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0364-20.2020 · Cited by 16 · see citing works
Wang, Z., Yuan, Y., Jiang, Y., You, J., & Zhang, Z. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110192 · Cited by 13 · see citing works
Self-citationBouts, M. J. R. J., van der Grond, J., Vernooij, M. W., Koini, M., Schouten, T. M., de Vos, F., Feis, R. A., Cremers, L. G. M., Lechner, A., Schmidt, R., et al. (2019) · Human Brain Mapping · doi:10.1002/hbm.24554 · Cited by 11 · see citing works
Harı, E., Kizilates-Evin, G., Kurt, E., Bayram, A., Ulaşoğlu-Yıldız, Ç., Gurvit, H. I., & Demıralp, T. (2023) · Clinical Neurophysiology · doi:10.1016/j.clinph.2023.06.008 · Cited by 11 · see citing works
Liu, Y., Liu, D., Liu, M., Li, K., Shi, Q., Wang, C., Pan, Z., & Zhou, L. (2022) · Neurological Sciences · doi:10.1007/s10072-022-06408-x · Cited by 9 · see citing works
Self-citationGogniat, M. A., Mewborn, C. M., Robinson, T. L., Jean, K. R., & Miller, L. S. (2021) · Journal of Physical Activity and Health · doi:10.1123/jpah.2021-0012 · Cited by 9 · see citing works
Groechel, R. C., Alosco, M. L., Dixon, D. B., Tripodis, Y., Mez, J. B., Goldstein, L. E., Budson, A. E., Qiu, W. Q., & Killiany, R. (2023) · The Journal of Comparative Neurology · doi:10.1002/cne.25564 · Cited by 3 · see citing works
Wang, Z., Zhang, Z.-S., Xie, C., Shu, H., Liu, D., & Zhang, Z.-J. (2021) · Journal of Alzheimer's Disease · doi:10.3233/jad-210579 · Cited by 4 · see citing works
Self-citationZhang, Z., Wang, M., Lü, T., Shi, Y., Xie, C., Ren, Q., & Wang, Z. (2024) · Brain Communications · doi:10.1093/braincomms/fcaf033 · Cited by 1 · see citing works
Self-citationWang, Z., Shu, H., Liu, D., Su, F., Xie, C., Cui, Z., & Zhang, Z. (2020) · doi:10.21203/rs.3.rs-31020/v2 · Cited by 1 · see citing works
Self-citationWang, Z., Shu, H., Liu, D., Su, F., Xie, C., Cui, Z., & Zhang, Z. (2020) · doi:10.21203/rs.3.rs-31020/v1
Self-citationWu, N., Zhu, S., Wu, Z., Shao, Y., Wang, P. F., Zhu, Z., Zhang, C., Wu, C., Huo, X., Lin, H., et al. (2025) · AIP Advances · doi:10.1063/5.0279891
Reas, E. T., Triebswetter, C., Banks, S. J., & McEvoy, L. K. (2024) · Figshare · doi:10.6084/m9.figshare.24987857
Wardana, N. D., Enriquez‐Geppert, S., Deyn, P. P. D., Marsman, J.-B. C., Reesink, F. E., Aleman, A., & Ćurĉić‐Blake, B. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877251411478
- Authors
- Wang, Z., Dai, Z., Shu, H., Liu, D., Guo, Q., He, Y., & Zhang, Z.
- Affiliations
- Zhongda Hospital Southeast University (CN)
- Sun Yat-sen University (CN)
- Fudan University (CN)
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
- Corresponding author
- Zhang, Zhijun
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2016-11-29
- Volume
- 56
- Issue
- 1
- Pages
- 415-428
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2559739875
- Cited by
- 26
- References
- 85
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 2
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- amnestic mild cognitive impairment, APOE ε4
- MeSH terms
- Aged, Aged, 80 and over, Apolipoproteins E, Atrophy, Cerebral Cortex, Female, Genotype, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Neuropsychological Tests, ROC Curve, Statistics, Nonparametric, Diffusion Magnetic Resonance Imaging, Cognitive Dysfunction, White Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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