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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]