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Table 1 Studies examining the apolipoprotein E polymorphisms ε2/ε3/ε4 and white matter integrity using diffusion magnetic resonance imaging

From: White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes

Reference (year) Methods Measures Sample size Age (years) Genotype groups Homozygotes (no.) Results
Nierenberg et al. (2005) [16] ROI FA, AxD, RD 29 67.1 (6.5) 14 ε4 carriers
15 ε4 noncarriers
2 ε4 carriers: ↓ FA and ↑ RD in L parahippocampal gyrus
(p = 0.015)
Persson et al. (2006) [17] ROI, SPM-VBM FA 60 66.3 (7.7) Two analyses:
10 ε4/ε4–10 ε3/ε4–10 ε3/ε3
30 ε4 carriers, 30 ε3/ε3
10 ↓ FA in ε4 carriers: Posterior corpus callosum and
fronto-occipital fasciculus
No evidence of dose-dependent effect, but not enough data
Honea et al. (2009) [15] TBSS FA 53 73.4 (6.3)
> 60
39 ε3/ε3
12 ε3/ε4
2 ε4/ε4
2 ↓ FA in ε4 carriers: L parahippocampal gyrus (p < 0.001
uncorrected)
Smith et al. (2010) [51] TBSS FA 65 62.9 (1.3) 42 ε4 carriers
23 ε4 noncarriers
n/a ↓ FA in LOAD risk group in many regions (e.g., bilateral
inferior fronto-occipital fasciculus, cingulum bundle, splenium) (p < 0.01)
Gold et al. (2010) [42] TBSS MD, FA, RD, AxD 57 58.9 (5.8) 37 ε4 carriers with FH
20 ε4 noncarriers without FH
n/a Significant for LOAD risk group only: ↓ FA ↑ RD: inferior longitudinal fasciculus, inferior fronto-occipital fasciculus/uncinate fasciculus (p < 0.001)
↓ FA: Fornix, ↑ MD: Genu and R inferior fronto-occipital fasciculus/inferior longitudinal fasciculus, ↓ AD: Cingulum
Bendlin et al. (2010) [30] SPM-VBM FA, MD 136 69.2 (10.2) 56 ε4 carriers
80 ε4 noncarriers
n/a No significant interactions between genotype and age were observed
ε4 allele: not significant
Family history LOAD + ε4: ↓ FA in multiple brain regions
Heise et al. (2011) [14] TBSS MD, FA, RD, AxD 73 (1) Young 28.6 (4.2) (2) Older: 64.9 (7.19) 17 ε4 carriers, 17 ε4 noncarriers (younger)
16 ε4 carriers, 21 ε4 noncarriers (older)
n/a ε4 carriers: ↑ MD (older) and ↓ FA (younger) in many regions (e.g., cingulum, corpus callosum) (p < 0.05)
Ryan et al. (2011) [12] ROI FA, ADC 126 CN (52–92) 88 ε4 noncarriers
32 ε4 heterozygotes
6 ε4/ε4
6 ε4 carriers: ↑ ADC with ↑ age in all regions (p < 0.0001)
↓ FA with ↑ age: Frontal, and temporal WM, genu (p < 0.05)
Westlye et al. (2012) [18] TBSS MD, FA, RD, AxD 203 47.6 (14.9)
21.1–69.9
30 ε2/ε3
113 ε3/ε3
60 ε3/ε4
0 ε4 carriers: widespread increases in MD and RD
no interaction between age and genotype
no significant differences between ε2/ε3 and ε3/ε4
Adluru et al. (2014) [20] ROI MD, FA, RD, AxD 343 61.03 (6.72)
47–76
14 ε4/ε4
109 ε4 heterozygotes
220 ε4 noncarriers
14 Subjects with FH: higher AxD in ε4 carriers, lower AxD in ε4 non-carriers, both in the uncinate fasciculus
ε4 carriers: higher MD in the SLF (older) and in the portion of the cingulum bundle running adjacent to the cingulate cortex, also higher RD in the genu
Kljajevic et al. (2014) [62] ROI FA, MD 56 67.7 (5.9) 28 ε4 carriers, 28 ε4 noncarriers n/a ε4 carriers: higher MD in healthy controls but not in AD (p < 0.001, uncorrected)
Lyall et al. (2014) [63] ROI FA 645 72.70 (0.74) 2 ε2/ε2
77 ε2/ε3
14 ε2/ε4
376 ε3/ε3
160 ε3/ε4
13 ε4/ε4
13 ε4 carriers: lower FA in right ventral cingulum and left inferior longitudinal fasciculus
Laukka et al. (2015) [64] TBSS FA, MD 89 81.41 (3.01) 23 ε4 carriers, 66 ε4 noncarriers n/a ε4 carriers: lower FA in forceps major and higher MD in corticospinal tract
Cavedo et al. (2017) [19] TBSS MD, FA, RD, AxD 74 68.95 (6.85) 31 ε4 carriers, 43 ε4 noncarriers n/a ε4 carriers: lower FA and higher RD in the cingulum, corpus callosum, inferior fronto-occipital and in the inferior longitudinal fasciculi, also higher MD in the genu, right internal capsule, superior longitudinal fasciculus and corona radiata.
  1. Abbreviations: FH Family history, LOAD Late-onset Alzheimer’s disease, VBM Voxel-based morphometry, ADC Apparent diffusion coefficient
  2. Adapted from [33]