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. 2019:22:101744.
doi: 10.1016/j.nicl.2019.101744. Epub 2019 Mar 4.

Applying surface-based hippocampal morphometry to study APOE-E4 allele dose effects in cognitively unimpaired subjects

Qunxi Dong  1 , Wen Zhang  1 , Jianfeng Wu  1 , Bolun Li  1 , Emily H Schron  2 , Travis McMahon  1 , Jie Shi  1 , Boris A Gutman  3 , Kewei Chen  4 , Leslie C Baxter  5 , Paul M Thompson  6 , Eric M Reiman  4 , Richard J Caselli  7 , Yalin Wang  8
Affiliations

Applying surface-based hippocampal morphometry to study APOE-E4 allele dose effects in cognitively unimpaired subjects

Qunxi Dong et al. Neuroimage Clin. 2019.

Abstract

Apolipoprotein E (APOE) e4 is the major genetic risk factor for late-onset Alzheimer's disease (AD). The dose-dependent impact of this allele on hippocampal volumes has been documented, but its influence on general hippocampal morphology in cognitively unimpaired individuals is still elusive. Capitalizing on the study of a large number of cognitively unimpaired late middle aged and older adults with two, one and no APOE-e4 alleles, the current study aims to characterize the ability of our automated surface-based hippocampal morphometry algorithm to distinguish between these three levels of genetic risk for AD and demonstrate its superiority to a commonly used hippocampal volume measurement. We examined the APOE-e4 dose effect on cross-sectional hippocampal morphology analysis in a magnetic resonance imaging (MRI) database of 117 cognitively unimpaired subjects aged between 50 and 85 years (mean = 57.4, SD = 6.3), including 36 heterozygotes (e3/e4), 37 homozygotes (e4/e4) and 44 non-carriers (e3/e3). The proposed automated framework includes hippocampal surface segmentation and reconstruction, higher-order hippocampal surface correspondence computation, and hippocampal surface deformation analysis with multivariate statistics. In our experiments, the surface-based method identified APOE-e4 dose effects on the left hippocampal morphology. Compared to the widely-used hippocampal volume measure, our hippocampal morphometry statistics showed greater statistical power by distinguishing cognitively unimpaired subjects with two, one, and no APOE-e4 alleles. Our findings mirrored previous studies showing that APOE-e4 has a dose effect on the acceleration of brain structure deformities. The results indicated that the proposed surface-based hippocampal morphometry measure is a potential preclinical AD imaging biomarker for cognitively unimpaired individuals.

Keywords: APOE-e4; Alzheimer's disease; Cognitively unimpaired; Hippocampal morphometry; Magnetic resonance imaging (MRI).

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Figures

Fig. 1
Fig. 1
The pipeline of hippocampal morphometry analysis: (A) Hippocampi were automatically registered and segmented with FIRST (FMRIB's integrated registration and segmentation tool) (Patenaude et al., 2011); (B) Triangular surface meshes were constructed based on the extracted hippocampal volumes; (C) Each hippocampal surface mesh was parameterized on the refined triangular mesh and then registered to a common template for morphometric features extraction. Eventually, the group differences of hippocampal morphometry were statistically analyzed between different APOE genotype groups.
Fig. 2
Fig. 2
Group hippocampal shape differences between APOE-e4 allele (e3/e4 and e4/e4, N = 73) and NC (e3/e3, N = 44) on the cognitively unimpaired individuals, at the nominal 0.05 level, uncorrected. The overall significance of LH with permutation test was p < .02. However, the overall significance of RH with permutation test was not significant (p > .05). LH: left hippocampus; RH: right hippocampus; NC: non-carriers.
Fig. 3
Fig. 3
Group hippocampal shape differences between HM (e4/e4, N = 37) and HT (e3/e4, N = 36) in the cognitively unimpaired cohort, at the nominal 0.05 level, uncorrected. The overall significance of LH with permutation test was p < .01. The overall significance of RH with permutation test was p < .01. LH: left hippocampus; RH: right hippocampus; HM: homozygotes; HT: heterozygotes.
Fig. 4
Fig. 4
Group hippocampal shape differences between HT (e3/e4, N = 36) /HM (e4/e4, N = 37) and NC (e3/e3, N = 44) on the cognitively unimpaired cohort, at the nominal 0.05 level, uncorrected. (A) Between NC and HE, the overall significances after multiple comparisons with permutation test were PLH = 0.0296 and PRH = 0.3579. (B) Between NC and HM, the overall significances after multiple comparisons with permutation test were PLH = 0.0105 and PRH = 0.1886. LH: left hippocampus; RH: right hippocampus; HT: heterozygotes; HM: homozygotes; NC: no-carriers.
Fig. 5
Fig. 5
Illustrations of the directional deformations of the significant hippocampal regions of APOE-e4 carriers (e3/e4 and e4/e4, N = 73) compared to NC (e3/e3, N = 44; A), of HM (e4/e4, N = 37) compared to HT (e3/e4, N = 36; B), of HT (e3/e4, N = 36) compared to NC (e3/e3, N = 44; C), and of HM (e4/e4, N = 37) compared to NC (e3/e3, N = 44; D) in the cognitively unimpaired subjects. Red and green colors show vertices with significant atrophies and expansions of APOE-e4 carriers compared to NC at the nominal 0.05 level, uncorrected for multiple comparisons. LH: left hippocampus; RH: right hippocampus; NC: non-carriers.
Fig. 6
Fig. 6
Cumulative distribution functions of the p-values from the LH morphometric comparisons of NC vs. e4-carriers, NC vs. HM, NC vs. HT and HT vs. HM, plotted against the expected p-values under the null hypothesis of no group differences among the comparisons. In false discovery rate methods, any cumulative distribution plot that rises steeply is a sign of a significant signal being detected, with curves that rise faster denoting higher effect sizes. The steep rise of the cumulative plot relative to p-values that would be expected by chance can be used to compare the detection sensitivity of different statistics derived from the same data. The deviations of the statistics from the null distribution generally increased from NC vs. HT to NC vs. HM in the cognitively unimpaired individuals study, suggesting that the APOE-e4 allele dose may be associated with faster atrophy of the LH. LH: left hippocampus; NC: no-carriers; HT: heterozygotes; HM: homozygotes.
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