Table 1.
Summary of sample characteristics, methodology and main findings for studies of APOE.
| Study | N (E4 carriers; non-carriers) | Age (SD) | dMRI Method | Field Strength (T) | B value (s/mm2) | Acquisition Voxel Size (mm) | N Directions | NEX | Regions of Interest | Results |
|---|---|---|---|---|---|---|---|---|---|---|
| Adluru et al, 2014 | 343 (123; 220) | 61.03 (6.72) | ROI | 3 | 0, 1300 | 2.5 × 2.5 × 2.5 | 40 | 1 | Fornix, splenium & genu of corpus callosum, cingulum, uncinate, superior longitudinal fasiculus. | • Older (>65) carriers vs. non-carriers: ↑MD in SLF & cingulum bundle |
| Bagepally et al, 2012 | 32 (19; 13) | 69.3 (5.7) | TBSS | 3 | 0, 1000 | Not reported | 32 | 1 | Whole brain | • AD carriers vs. AD non-carriers: ↓ FA in left medial temporal areas, parahippocampal cingulum, bilateral intracalcarine sulcus, precuneus, lingual area • Healthy carriers vs. healthy non-carriers: ↓ FA bilateral medial temporal areas, scattered regions in frontal & parietal lobes & cerebellum |
| Bendlin et al, 2010 | 136 (56; 80) | 69.2 (10.2) | VBA | 3 | 0 | 2 × 2 × 3 | 12 | 1 | Whole brain | • Carriers vs. non-carriers: no significant differences |
| Brown et al, 2011 | 55 (25; 30) | 62.3 (9.0) | Structural connectivity | 3 | 800 or 1000 | 2.5 × 2.5 × 2.5 | 30 | 1 | Global & regional connectivity | • Carriers vs. non-carriers: age-related loss of mean local interconnectivity, & regional local interconnectivity decreases in the precuneus, medial orbitofrontal cortex, & lateral parietal cortex. |
| Cai et al, 2017 | 309 (116; 193) | 73.9 (4.6) | VBA | 3 | Not reported | 1.02 × 1.02 × 1.02 | Not reported | 1 | Superior corona radiata, genu of corpus callosum | • Carriers vs. non-carriers: ↑ MD in superior corona radiata, genu of corpus callosum. No significant associations with FA or RD |
| Cavedo et al, 2017 | 74 (31; 43) across 4 centres |
68.9 (6.9) | TBSS, VBA | 1.5 or 3 | 0, 1000 or 0, 800 | 2 × 2 × 2 or 1 × 1 × 2.4 |
12, 15, 20 or 60 | 1 | Whole brain | • Carriers vs. non-carriers: ↓ FA globally, and in genu, body & splenium of corpus callosum, internal capsule, external capsule, inferior fronto-occipital & inferior longitudinal fasciculi, cingulum (left & right). ↑ MD in right hemisphere, in genu of corpus callosum, right internal capsule, right corona radiate, right superior longitudinal fasiculus. ↑ RD globally, & bilaterally in genu & splenium of corpus callosum, internal capsule, inferior fronto-occipital & inferior longitudinal fasciculi, cingulum, external capsule |
| Chen et al, 2016 | 75 (35; 40) | 65.8 (7.5) | Structural connectivity | 3 | 0, 1000 | Not reported | 30 | 3 | Whole brain structural network | • Carriers vs. controls: lower global efficiency, no significant differences in local efficiency. Decreased nodal efficiency in left anterior cingulate, left paracingulate gyrus, right dorsolateral superior frontal gyrus, left inferior occipital gyrus • Case/control prediction: ROC AUC for global efficiency 0.74; decreasing region 0.81 |
| Dell'Acqua et al, 2015 | 575 (119; 374) | 14.4 (0.5) | TBSS | 3 | 0, 1300 | 2.4 × 2.4 × 2.4 | 60 | 1 | Whole brain | • Carriers vs. non-carriers: no significant differences |
| Dowell et al, 2013 | 41 (20; 21) | 20.0 (2.0) | TBSS | 1.5 | 0, 1000 | 2.5 × 2.5 × 2.5 | 30 | 1 | Whole brain | • Carriers vs. controls: ↑ RD in carriers, partidcularly in inferior longitudinal fasciculus. No significant differences in FA or MD. |
| Heise et al, 2010 | 71 (33; 38) | Young cohort 28.6 (4.2); Older cohort: 64.9 (7.2) |
TBSS | 1000 | 1.1 × 0.9 × 3 | 1 | Whole brain | • Young carriers vs. non-carriers: ↓ FA in cingulum, corona radiata, corpus callosum, external capsule, internal capsule, superior longitudinal fasciculus • Older carriers vs. non-carriers: ↑ MD in cingulum, corona radiata, corpus callosum, external capsule, internal capsule, superior longitudinal fasciculus • All carriers vs. non-carriers: ↓ FA in cingulum, corona radiata, corpus callosum, external capsule, internal capsule, superior longitudinal fasciculus |
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| Honea et al, 2009 | 53 (14; 39) | 73.4 (6.3) | TBSS | 3 | 0, 1000 | 1 × 1 × 1 | 12 | 1 | Whole brain | • Carriers vs. non-carriers: no significant differences |
| Kljajevic et al, 2014 | 126 (63; 63) across 5 centres |
67.7 (5.9) | VBA | 1.5 + 3 | 0, 800 or 0, 1000 | 2 × 2 × 2, 2 × 2 × 2.5 or 2 × 2 × 3 |
6 or 20 | 1 | Whole brain | • Healthy carriers vs. healthy non-carriers: ↑ MD in left lentiform nucleus • AD carriers & AD non-carriers: ↓ FA in middle frontal areas, insular white matter, superior temporal areas |
| Laukka et al, 2015 | 89 (23; 66) | 81.4 (3.0) | TBSS | 1.5 | 600 | 1 × 1 × 1 | 6 | 1 | Cingulate gyrus part of cingulum, parahippocampal cingulum, corticospinal tract, forceps major & minor, inferior fronto-occipital fasciculus, superior longitudinal fasciculus | • Carriers vs. non-carriers: ↓ FA in forceps major, ↑ MD in corticospinal tract |
| Lyall et al, 2014 | 645 (187; 423) | 72.7 (0.7) | ROI | 1.5 | 0, 1000 | 1.8 × 1.8 × 1.8 | 64 | 1 | Genu & splenium of corpus callosum, bilateral anterior thalamic radiations, ventral & rostral cingulum bundles, & arcuate, uncinate, & inferior longitudinal fasciculi. | • Carriers vs. non-carriers: ↓ FA in right ventral cingulum & left inferior longitudinal fasciculus |
| Ma et al, 2017 | 885 (145; 729) | 65.3 (7.4) | Structural connectivity | 3 T | 1000 | Not reported | 30 | 1 | Whole brain structural network | •Healthy carriers vs healthy non-carriers: ↑ clustering coefficient & local efficiency • MCI carriers vs. non-carriers: ↓ clustering coefficient & local efficiency • All carriers vs. non-carriers: ↓ nodal efficiency in: inferior frontal gyrus, orbital part; left superior frontal gyrus, orbital part; left middle occipital gyrus. ↑ nodal efficiency in: left cuneus; left inferior parietal but supramarginal and angular gyri |
| Newlander et al, 2014 | 14 (7; 7) | 72.7 (6.1) | VBA | 1.5 | 0, 800 | 1 × 1 × 1 | 12 | 1 | Whole brain | • Carriers vs. non-carriers: ↓ FA in genu of corpus callosum & brain stem |
| Nierenberg et al, 2005 | 29 (14; 15) | 67.1 (6.5) | ROI | 1.5 | 0, 1000 | Not reported | 20 | 1 | Parahippocampal cingulum | • Carriers vs. non-carriers: ↓ FA & ↑ RD in parahippocampal cingulum |
| Nyberg et al, 2014 | 273 (69; 204) | 67.01 (8.0) | TBSS, VBA | 3 | 1000 | 0.98 × 0.98 × 2 | 32 | 1 | Whole brain | • Carriers vs. controls: no significant difference for whole brain metrics or specific subregion metrics in TBSS. ↓ FA in five anterior and posterior midline regions on VBA |
| O'Dwyer et al, 2012 | 44 (22; 22) | 26.7 (4.0) | TBSS | 3 | 1000 | 2 × 2 × 2 | 60 | 1 | Whole brain | • Carrier vs. non-carrier: no significant differences in diffusion indices • Carrier/non-carrier prediction accuracy: sensitivity & specificity range 93–100% using a feature selection algorithm, support vector machines & FA data |
| Operto et al, 2018 | 532 (275; 257) | 58.1 (7.5) | TBSS | 3 | 0, 1000 | 2 × 2 × 2 | 64 | 1 | Whole brain | • Carriers vs. non-carriers: ↑ MD, RD & LD in corona radiata, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract |
| Persson et al, 2006 | 60 (30; 30) | 66.3 (7.7) | ROI | Not reported | 1000 | Not reported | 6 | 1 | Whole brain analysis; genu, splenium, body of corpus callosum | • Carriers vs. non-carriers: ↓ FA in occipito-frontal fasciculus, body of corpus callosum |
| Ryan et al, 2011 | 126 (36; 88) | 69.2 (10.2) | ROI | 3 | 0, 1000 | 2.6 × 2.6 × 2.6 | 25 | 2 | Frontal white matter, lateral parietal white matter, centrum semiovale, genu of the corpus callosum, splenium of the corpus callosum, temporal stem white matter. | • Carriers vs. non-carriers: no significant difference in LD, ↓ FA in frontal white matter & splenium |
| Salminen et al, 2013 | 64 (23; 41) | 61.75 (7.6) | ROI | 3 | 0, 996 | 2 × 2 × 2 | 31 | 1 | Left uncinate fasciculus, right uncinate fasciculus, temporal lobe | • Carriers vs. controls: ↓ fibre bundle length in left uncinate fasciculus |
| Slattery et al, 2017 | 37 (22; 15) | 61.7 (5.0) | TBSS, ROI | 3 | 1000 | 2.5 × 2.5 × 2.5 | 64 | 1 | Quadrants (anterior, posterior, left & right) | • AD carriers vs. AD non-carriers: ↓ FA in splenium of corpus callosum & anterior corona radiata. ↑ RD in white-matter projections from frontal lobes. More widespread ↓ NDI in parieto-occipital white-matter projections. ↑ FISO in corpus callosum • Healthy carriers vs. non-carriers: no significant differences |
| Smith et al, 2016 | 88 (34; 53) | 74.1 (4.5) | TBSS | 3 | 0, 1000 | 1 × 1 × 1 | 25 | 2 | Longitudinal fasciculus, sagittal stratum, uncinate fasciculus, cingulate gyrus, parahippocampal cingulumfornix, body, genum & splenium of corpus callosum, internal capsule, corona radiata | • Carriers vs. non-carriers: no significant effects on FA, LD or MD. ↑ RD in right anterior internal capsule, bilateral posterior corona radiata, left superior corona radiata. |
| Wai et al, 2014 | 120 (22; 98) | 68.9 (7.7) | TBSS | 3 | 1000 | 2 × 2 × 2 | 64 | 1 | Whole brain | • Amnestic MCI carriers vs. controls: ↓ FA & ↑ MD |
| Wang et al, 2015 | 241 (73; 126) | 72.0 (9.0) | TBSS | 1.5 | 0, 600 | 1 × 1 × 1 | 6 | 1 | Whole brain | • Carriers vs. non-carriers: no significant differences |
| Westlye et al, 2012 | 203 (60; 143) | 47.6 (14.9) | TBSS | 1.5 | 1000 | 2 × 2 × 2 | 60 | 1 | Whole brain | • Carriers vs. non-carriers: increased RD brainstem, basal temporal lobe, internal capsule, anterior parts of the corpus callosum, forceps minor, superior longitudinal fasciculus, occipital & corticospinal pathways. |
| Zhang et al, 2015 | 75 (35; 40) | 65.9 (7.5) | TBSS, VBA | 3 | 0, 1000 | 2 × 2 × 2 | 30 | 1 | Genu, body, splenium of corpus callosum, anterior & posterior corona radiate, fornix, cerebral peduncles, parahippocampal cingulum | • Carriers vs. non-carriers: ↓ FA & ↑ MD in genu & body or corpus callosum, anterior & posterior corona radiate bilaterally with TBSS. ↓ FA in genu and body of corpus callosum & right fornix stria terminalis , ↑ MD in genu & splenium of corpus callosum, right cerebral penduncle & right parahippocampal cingulum with VBA |
Please note that we report findings from the most rigorous analyses conducted by studies, including models controlling for multiple comparisons. When not otherwise reported, NEX was assumed to be 1. Acronyms: dMRI = diffusion Magnetic Resonance Imaging; E4 = APOE Epsilon 4; TBSS = Tract-Based Spatial Statistics; VBA = Voxel-Based Analysis; ROI = Region of Interest; FA = Fractional Anisotropy; MD = Mean Diffusivity; RD = Radial Diffusivity; LD = Longitudinal Diffusivity; NDI = Neurite Dispersion Index; FISO = Free Isotropic Water Fraction; ROC = Receiver Operating Characteristic; AUC = Area Under Curve.