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The APOE ε4 allele modulates brain white matter integrity in healthy adults
*Verena Heise, MSc
1,2
, *Nicola Filippini, PhD
1,2,3
, Klaus P. Ebmeier, MD
1,2
,
Clare E. Mackay, PhD
1,2,a
1
FMRIB, Oxford Centre for Functional Magnetic Resonance Imaging of the
Brain, and
2
University Department of Psychiatry, University of Oxford, Oxford,
UK;
3
LENITEM, Laboratory of Epidemiology, Neuroimaging, & Telemedicine-
IRCCS S. Giovanni di Dio-FBF, Brescia, Italy
*These authors contributed equally
a
Correspondence:
Dr Clare Mackay, FMRIB, University of Oxford, John Radcliffe Hospital,
Headley Way, Headington, Oxford, OX3 9DU, UK
Phone: +44 (0)1865-222-494
Fax: +44 (0)1865-222-717
E-mail: clare.mackay@psych.ox.ac.uk
peer-00574005, version 1 - 7 Mar 2011
Author manuscript, published in "Molecular Psychiatry (2010)"
DOI : 10.1038/mp.2010.90
Abstract
The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk
factor for sporadic Alzheimer’s disease (AD) and is also associated with
structural gray matter (GM) and functional brain changes in healthy young,
middle-aged and elderly subjects. Because APOE is implicated in brain
mechanisms associated with white matter (WM) development and repair, we
investigated the potential role played by the APOE polymorphism on WM
structure in healthy younger (age range: 20-35 years) and older (aged 50-78
years) adults using diffusion tensor imaging (DTI). General reduction of
fractional anisotropy (FA) and increase in mean diffusivity (MD) values was
found in carriers of the APOE ε4 allele relative to non-carriers. No significant
interactions between genotype and age were observed, suggesting that
differences in WM structure between APOE ε4-carriers and non-carriers do
not undergo significant differential changes with age. This result was not
explained by differences in brain morphology or cognitive measures. The
APOE ε4 allele modulates brain WM structure before any clinical or
neurophysiological expression of impending disease.
Keywords
APOE, diffusion tensor imaging, neuroimaging, white matter, healthy subjects,
aging
peer-00574005, version 1 - 7 Mar 2011
Introduction
Apolipoprotein E (apoE, protein; APOE, gene) is a very-low-density lipoprotein
that has a key role in coordinating the mobilization and redistribution of
cholesterol, phospholipids, and fatty acids.
1
In the central nervous system,
apoE is implicated in mechanisms such as neuronal development, brain
plasticity, and repair functions.
2,3
The human APOE gene has 3 allelic variants
(ε2, ε3, and ε4). The ε4 allele is associated with higher risk of developing both
early-onset
4
and late-onset
5
Alzheimer's disease (AD), poor outcome from
traumatic brain injury
6
and age-related cognitive impairment.
7
Neuroimaging studies have shown that the APOE ε4 allele is associated with
modification of brain function and gray matter (GM) structure, both in AD
patients
8,9,10
and in healthy subjects.
11,12,13,14,15
GM volume reduction in AD
patients carrying the ε4 allele relative to non-carriers has been found mainly in
the hippocampus and entorhinal cortex.
8,10,16,17
Similarly, reductions in MTL
volumes have been reported among healthy middle-aged/ elderly,
18,19,20,21
and
adolescent
22
APOE ε4-carriers, although not all studies replicate this
finding.
23,24,25
Positron emission tomography (PET) studies have consistently
shown resting glucose metabolism reduction in healthy young and middle-
aged APOE ε4-carriers in brain regions known to be affected by AD
pathology, such as the parietal, temporal and prefrontal cortices.
12,13
Task-
based functional magnetic resonance imaging (fMRI) studies have been less
consistent, showing increased
11,14,15
, decreased
26,27
or even no difference
28
in
task-related BOLD signal between healthy APOE ε4-carriers and non-carriers.
Methodological differences may explain inconsistencies in the studies.
Because of the link between APOE and AD, to date structural imaging studies
have largely concentrated on GM changes, especially in the entorhinal cortex
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and hippocampal regions, which are the first structures to show AD
pathology.
29
Very few studies have investigated the potential effects of the
APOE genotype on white matter (WM) structure. This is surprising considering
that the major role of apoE in the brain is the transport of lipid components
which contribute to building up the myelin sheath.
30,31,32
Moreover, AD
pathology not only involves GM atrophy but also changes in WM
33
, which
have been shown to correlate with disease severity.
34,35
Diffusion tensor
imaging (DTI) is an imaging technique that is increasingly used for WM
analysis in vivo. DTI-derived measurements, such as fractional anisotropy
(FA) and mean diffusivity (MD), have proved to be sensitive for detection of
disease-related WM changes.
36
A recent meta-analysis of DTI measurements
in AD and MCI reported widespread increases in MD and decreases in FA
with large effect sizes.
37
To date studies using DTI to investigate the effects of
APOE on FA and MD have focused on specific age groups
38
or were limited to
preselected regions-of-interest.
39
The aim of this study is to investigate the
relationship between APOE genotype, WM structure and age in healthy
individuals using an unbiased whole-brain analysis (tract-based spatial
statistics - TBSS
40
) using DTI. This will allow us to investigate whether the ε4
allele selectively modulates well-defined WM pathways or rather has a more
general effect. In particular, we will test whether the APOE ε4 allele alters WM
integrity both in distinct groups of younger (age range = 20 to 35 years old)
and older (age range = 50 to 78 years old) participants.
Based on previously reported studies showing age-related WM changes in
healthy subjects
41,42,43,44
, we hypothesize that older subjects will have
increased MD and reduced FA. As the APOE ε4 allele is associated with an
earlier onset of AD
4
and cognitive decline at a younger age
7
, we expect that
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the trajectories of WM changes with age will differ between APOE ε4-carriers
and non-carriers. Moreover, we will study GM volumes to investigate whether
whole brain GM or WM analyses are more sensitive to changes associated
with the APOE ε4 allele. Based on previous studies
20
, we hypothesize that
GM volume will be reduced in older APOE ε4-carriers. Lastly, we will compare
the data between younger and older groups to study a possible interaction
between age and genotype. We will test alternative hypotheses: either brain
structure of APOE ε4-carriers already differs from non-carriers in young
adulthood, or structural modifications associated with the APOE ε4 allele only
manifest at a certain age, perhaps preceding AD development in healthy
adults.
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Materials and methods
Participants: Imaging data for 73 right-handed subjects (35 males) aged 20
to 78 years were acquired. Thirty-four subjects aged 20 to 35 years comprised
the “younger” group (mean age 28.6 years ± 4.20), and thirty-nine subjects
aged 50 to 78 years (mean 64.9 years ± 7.19) comprised the “older” group.
A priori exclusion criteria were: current or past history of neurological or
psychiatric disorders, memory complaints, head injury, substance abuse
(including alcohol), corticosteroid therapy, and youth diabetes therapy. A
posteriori (after MRI scan) exclusion criteria included presence of brain
vascular insults and two or more hyperintense lesions equal or larger than 10
mm diameter, or more than eight hyperintense lesions with a diameter from 5
to 9 mm
45
, on a Fluid Attenuated Inversion Recovery (FLAIR) image. In order
to exclude possible confounds due to cognitive complaints older subjects
underwent a pre-screening cognitive test [Addenbrooke’s Cognitive
Examination-revised version (ACE-R)
46
].
Subjects were pre-screened for APOE genotype (using a cheek swab sample)
and selected for the study on the basis of either having an APOE ε4 allele
(APOE ε4-carrier) or being an ε3 homozygote (non-carrier). Three APOE ε4-
carriers were homozygous for the ε4 allele (one in the younger and two in the
older group). The genotyping process was conducted at the Wellcome Trust
Centre for Human Genetics in Oxford. DNA was extracted from cheek swab
samples of subjects according to standard procedures to allow PCR for the
characterization of APOE genotype. The study was approved by the local
Ethics Committee, and written informed consent was signed by all
participants.
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Image Acquisition: Scans were performed at the University of Oxford Centre
for Clinical Magnetic Resonance Research (OCMR) using a 3-T Siemens Trio
scanner (Siemens AG, Erlangen, Germany) with a 12-channel head coil. The
neuroimaging protocol included a 3D T1-weighted structural scan (TR = 2040
ms, TE = 4.7 ms, flip angle = 8°, field of view = 192 mm, voxel dimension = 1
mm isotropic, acquisition time = 12 min), diffusion weighted imaging (echo
planar imaging, TR = 9300 ms, TE = 94 ms, field of view = 192 mm, voxel
dimension = 2 mm isotropic, B-value = 1000, gradients applied = 60
isotropically distributed, acquisition time = 21 min) and fluid attenuated
inversion recovery (FLAIR) imaging (TR = 9000 ms, TE = 89 ms, field of view
= 220 mm, voxel dimension = 1.1x0.9x3 mm, acquisition time = 5 min 8 sec).
Image Analysis: Data analysis was carried out using FMRIB Software Library
(FSL) tools (www.fmrib.ox.ac.uk/fsl
).
Diffusion Tensor Imaging (DTI):
Raw images were pre-processed using “Eddy
Current correction”, in order to correct for distortions due to the gradient
directions applied. Fractional anisotropy (FA) and mean diffusivity (MD) maps
were generated using DTIFit, part of FMRIB’s Diffusion Toolbox
(http://www.fmrib.ox.ac.uk/fsl/fdt), that fits a diffusion tensor model at each
voxel
47
. The magnitude and direction of tissue water mobility is measured in
the three dimensions
48
and the diffusion tensor is modelled as an ellipsoid
with symmetry across any one of its three axes. The largest axis or eigenvalue
is denoted λ1 or axial diffusivity. The two minor axes (λ2, λ3) are usually
averaged to compute radial diffusivity. The average of all three eigenvalues is
called mean diffusivity (MD). Fractional anisotropy (FA) is a ratio of axial to
radial diffusivity, and thus provides a measure of the directionality of diffusion.
In axons, net intravoxel water diffusion perpendicular to the fibres is reduced
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due to the myelin sheath but unrestricted parallel to the axon. This
directionality of water diffusion gives rise to a higher FA in WM, whereas less
restricted diffusion, e.g. in GM or cerebrospinal fluid leads to lower FA. GM
and WM have similar MD values.
The FA output images were used as input for tract-based spatial statistics
(TBSS), a voxelwise approach for analysis of FA data.
40
All subjects' FA data
were aligned into a common space using the nonlinear registration tool
FNIRT. The mean FA image was generated and thinned to create a mean FA
skeleton, which represents the centres of all tracts common to the group.
Each subject's aligned FA data was then projected onto this skeleton and the
resulting data fed into voxelwise GLM cross-subject statistics. A voxel by voxel
permutation nonparametric test (5000 permutations) was used to assess
group-related differences using threshold-free cluster enhancement (TFCE),
which avoids using an arbitrary threshold for the initial cluster-formation.
40
All
results are shown at p < 0.05 corrected for multiple comparisons across
space. In addition to FA data, mean diffusivity (MD), axial diffusivity (DA) and
radial diffusivity (DR) were also compared using TBSS in an analogous
fashion. Separate analyses were performed for the younger and older group,
then data from both groups were pooled together. GM volume, WM volume
and cognitive scores were added to the TBSS analysis as covariates of no
interest.
Structural MRI:
A voxel-based morphometry (VBM) approach was used to
study brain morphology and to relate it to the APOE polymorphism. Total brain
volume, GM and WM and cerebrospinal fluid (CSF) measurements were
calculated using FMRIB’s Automated Segmentation Tool (FAST).
49
Whole-
brain analysis was carried out with FSL-VBM
50
, using default settings. In brief,
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brain extraction and tissue-type segmentation were performed, and resulting
GM or WM partial volume images were aligned to standard space using
FMRIB's Linear Image Registration Tool (FLIRT) and then nonlinear (FNIRT)
registration tools. The resulting images were averaged, modulated, and
smoothed with an isotropic Gaussian kernel of 3mm (~7 mm FWHM) to create
a study-specific template. Finally, voxelwise general linear modelling (GLM)
was applied using permutation nonparametric testing (5000 permutations) and
p < 0.05 correcting for multiple comparisons across space. GM volume and
total brain volume were used as covariates of no interest in the VBM analysis.
ROI analysis of hippocampal volume:
Individual hippocampal measures were
obtained using FMRIB’S Integrated Registration and Segmentation Tool
(FIRST), an automatic subcortical segmentation program.
51
Boundary
correction was used for the classification of the boundary voxels. ROIs were
visually inspected in the coronal plane to ensure accuracy.
White matter lesions:
Measurement of WM lesions in the older group was
manually performed on FLAIR by a trained neuroscientist (VH) blind to the
genotypic profile using the Jim 4.0 software (Xinapse Medical Systems,
Thorpe Waterville, UK). All axial slices of each subject were investigated for
WM hyperintensities and periventricular WM lesions. After marking all
hyperintensities and periventricular lesions as Regions-of-interest (ROIs), total
ROI volume was calculated for each subject.
Statistics:
Statistical analyses of non-imaging variables were carried out using
SPSS software (SPSS Inc., Chicago, USA). T-tests comparison were used for
continuous variables (sociodemographic, cognitive performance and brain
volumes). Exact Fisher's continuity correction was used for categorical
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variables (gender and family history of dementia). An alpha of p < 0.05 was
considered significant.
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Results
Participants: Seventy-three subjects completed the MRI protocol. Two of the
older subjects (one APOE ε4-carrier, one non-carrier) were excluded because
they showed an abnormally high volume of white matter lesions (more than 3
standard deviations from each group mean), leaving a total of 71 subjects
(Table 1). There was no effect of genotype on white matter lesion volume
(F
1,34
= 2.40, p = 0.13). Within the younger and older group, APOE ε4-carriers
and non-carriers did not differ for age, sex, years of education, number of
individuals with a family history of dementia and ACE-r results. Similarly,
memory performance and reaction times in an encoding memory task as
described in Filippini et al.
52
were not different between APOE ε4-carriers and
non-carriers (Table 1).
Diffusion tensor imaging (DTI):
In the younger group whole brain WM analysis
with TBSS revealed decreased FA values in APOE ε4-carriers relative to non-
carriers in widespread areas, including the cingulum, corona radiata, corpus
callosum, external capsule, internal capsule and superior longitudinal
fasciculus (Figure 1a). There were no regions in which FA values were higher
in APOE ε4-carriers relative to non-carriers. The decreased FA in APOE ε4-
carriers was not associated with significant differences in either MD, DA or
DR.
In the older group, whole brain analysis with TBSS showed increased MD in
APOE ε4-carriers relative to non-carriers in widespread areas including the
cingulum, corona radiata, corpus callosum, external capsule, internal capsule
and superior longitudinal fasciculus (Figure 1b) but there were no significant
differences in FA, DR or DA. There were no regions in which MD values were
lower in APOE ε4-carriers relative to non-carriers.
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TBSS analysis with the data from both age groups combined was performed
to study a possible interaction between AGE (younger or older) and
GENOTYPE (APOE ε4-carrier and non-carrier) factors. No significant
interaction between the two factors was detected for FA or MD. However, a
main effect of GENOTYPE was found for FA values in areas including the
cingulum, corona radiata, corpus callosum, external capsule, internal capsule
and superior longitudinal fasciculus (Figure 1c). Additionally, DR was
significantly higher in APOE ε4-carriers compared to non-carriers (Figure 1d)
but there were no significant effects on MD or DA.
As we expected, a widespread main effect of AGE was observed for FA. FA
was significantly increased in the younger compared to the older group in WM
tracts including the cingulum, corona radiata, corpus callosum, external
capsule, internal capsule and superior longitudinal fasciculus (Figure 4a). This
was associated with significantly increased DA and DR in the older group
(Figure 4c and d). The same structures showed significantly increased MD
values in the older group (Figure 4b). There were no regions in which FA
values were higher or MD, DA or DR values were lower in the older group
compared to the younger group.
Structural MRI:
No differences between APOE ε4-carriers and non-carriers in
both age groups were found for total brain volume, GM volume, WM volume,
cerebrospinal fluid (CSF) and hippocampal volumes (Table 1). Moreover, no
differences between APOE ε4-carriers and non-carriers were observed in GM
or WM using a whole brain Voxel-Based-Morphometry approach.
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Discussion
We investigated the effect of the APOE genotype on WM structure in healthy
individuals using Diffusion Tensor Imaging (DTI) and found that the APOE ε4
allele affects WM integrity. In detail, we observed significantly reduced FA
values in younger APOE ε4-carriers and increased MD in older ε4-carriers
relative to matched non-carriers in widespread areas of the brain. Reduced FA
values in APOE ε4-carriers relative to non-carriers were also found when the
data from both groups were combined. No significant interactions between
AGE and GENOTYPE were observed, suggesting that APOE has an effect on
WM that is evident even in early adulthood and remains relatively stable
throughout adulthood. Increased MD and decreased FA are generally markers
of pathology, thus our observation may provide clues to the basis of the
vulnerability of APOE ε4-carriers to late-life pathology.
EFFECT OF APOE GENOTYPE ON WM
This is the first study to describe an effect of the APOE ε4 allele on WM
structure in a group of healthy young adults. Whole-brain analysis showed that
young APOE ε4-carriers had reduced FA values in widespread brain areas.
Therefore carrying the APOE ε4 allele influences WM integrity even in young
adulthood. A genotype effect on WM structure was also found in the older
group. Although FA was not altered, widespread significant increases in MD
were observed in APOE ε4-carriers. This is in accordance with several other
studies that reported effects of the APOE ε4 allele on WM integrity in brain
tracts such as parahippocampal WM
38,53
and the corpus callosum
39,54
whereas
a recent study did not replicate these results
55
.
Although the APOE genotype affects different measures of WM integrity in the
two age groups, this is probably caused by age differences in FA and MD
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measures. It is possible that FA is more sensitive to detect differences in
younger adults because we found that FA values decrease with age
independent of genotype. The opposite effect would be found for MD.
AD and amnesic MCI are associated with an increased volume of WM lesions
compared to healthy controls
56,57
, which predicts the rate of cognitive
decline.
58
We did not find a significant effect of the APOE ε4 allele and this is
in concordance with two studies reporting an effect of APOE genotype on
volume of WM lesions only for homozygous individuals and no gene-dose
effect.
59,60
Although APOE genotype effects were observed within WM regions in both
the younger and the older group, we found that GM structure did not differ
between APOE ε4-carriers and non-carriers. This was interesting because we
expected that at least in the older group the higher risk of AD for APOE ε4-
carriers would show in GM changes, especially in regions affected early by
AD
61
, as was shown in two studies
20,53
. However, other studies also failed to
observe APOE-related structural GM differences in healthy subjects.
23,24,25
We
therefore suggest that brain function
11,12,13,14,15,52
and WM-related
measurements are more sensitive than GM-related measurements to detect
the physiological effects of carrying an APOE ε4 allele.
EFFECT OF AGE ON WM INTEGRITY
As expected, we found age-related changes in FA and MD. FA was
significantly lower in the older than in the younger group independent of APOE
genotype. In addition, a widespread increase in MD was found in the older
group. Several studies also observed reductions in FA with age mainly in
prefrontal structures
41,42,43
as well as changes in WM volume unevenly
distributed across brain regions.
44
Therefore, our results are similar to age-
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related changes in WM integrity observed by other groups and our unbiased
whole-brain approach strengthens these results.
INTERPRETATION
The main goal of our study was to investigate whether differences in WM
structure between APOE ε4-carriers and non-carriers change across the
lifespan. As TBSS revealed no significant AGE by GENOTYPE interactions for
FA or MD we showed that genotype-dependent differences in WM structure
are already present in young adulthood and do not undergo significant
differential changes with age. Previously, we have shown functional
differences between APOE ε4-carriers and non-carriers in the same group of
younger subjects.
52
It is possible that WM differences might underlie these
functional differences found in the default-mode network (DMN). Indeed, it has
been shown that structural connectivity between the cingulum, superior frontal
occipital fasciculus and genu of the corpus callosum determine the functional
links of the DMN.
62
We found that FA was significantly decreased in young
APOE ε4-carriers in the cingulum and genu of the corpus callosum. However,
the relationship between structural and functional differences between APOE
ε4-carriers and non-carriers require further investigation.
The effect of APOE on brain structure and function and the associated risk of
AD remains poorly understood. The major role of apoE in the brain is the
transport of lipid components which contribute to building up the myelin
sheath.
30,31,32
In-vitro and in-vivo studies have shown that the apoE isoforms
differentially modulate neuritic outgrowth, sprouting and branching
63,64,65
and
the apoE4 isoform has been specifically associated with microtubule
depolymerisation
65
and axonal degeneration
66
thus potentially affecting WM
integrity. Although these studies point to a differential role for the apoE
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isoforms on white matter structure, the molecular mechanisms require further
investigation.
LIMITATIONS AND FUTURE DIRECTIONS
Our cross-sectional study did not cover the entire lifespan but instead
concentrated on distinct age groups of younger (20-35 years) and older (50-78
years) volunteers. The age-related changes in WM that we observed are
unlikely to be caused by a cohort effect, but longitudinal studies would be
required to rule this out. Given our observation of white matter changes even
in young adulthood, it would be particularly interesting to investigate
differences in brain development of children and adolescents carrying the
APOE ε4 allele.
It is important to note that the changes in WM that we observe in APOE ε4-
carriers may not relate to AD risk because there are other genes in linkage
disequilibrium with APOE ε4 that might affect WM structure.
67
For example
APOC1 and TOMM40 have been associated with increased risk of AD
development
68
or earlier age of AD onset.
69
Large population samples would
be needed to study the contribution of other genes to WM structure and AD.
The link between APOE, WM structure and AD risk would be strengthened if
evidence of a gene-dose effect in WM integrity that mirrored the gene dose
effect in AD risk could be found. WM changes might prove to be a useful
imaging marker for early detection of subjects at increased risk of developing
AD. The methods for including imaging markers in genome wide association
studies are now being worked out.
70
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CONCLUSION
In conclusion, this study demonstrated that individuals carrying the APOE ε4
allelic variant have different WM-related measurements even at a young age
but show no differences in GM structure. No significant interactions of
genotype and age group were found indicating that differences in WM
structure between APOE ε4-carriers and non-carriers remain relatively stable
during adulthood. The WM changes we observed in young adults occur
decades before any impending cognitive or clinical manifestations of disease,
and are thus probably not caused by preclinical AD pathology. Nevertheless,
the changes we see mirror those found in early AD and MCI and may
therefore inform our understanding of the increased risk of disease in APOE
ε4-carriers.
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Acknowledgements
We thank Prof. Jonathan Flint and Amarjit Bhorma, Wellcome Trust Centre for
Human Genetics, for genotyping APOE data. VH was supported by the
Alzheimer’s Research Trust (English Charity Register: 1077089) and the
German National Academic Foundation (Studienstiftung des deutschen
Volkes), NF by the Gordon Edward Small’s Charitable Trust (Scottish Charity
Register: SC008962).
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Conflict of Interest
The authors declare no conflict of interest.
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Table 1 Sociodemographic features and general brain morphology of both
age groups. Values denote mean (±Standard Deviation) or number of
subjects, *Values are expressed as percentage of whole-brain volume; p-
values refer to t-tests (parametric data) and chi-square tests (categorical
data).
Younger group
APOE ε4 carriers
(N = 17)
APOE ε4 non-carriers
(N = 17)
P
Age [years]
28.88 (±4.69) 28.24 (±3.77) 0.66
Sex [Male / Female]
10 / 7 10 / 7 1.00
Education [years]
19.53 (±2.35) 19.41 (±1.91) 0.87
Family history of dementia
2 2 1.00
Encoding memory task (max 83)
70.88 (±8.17) 69.24 (±8.12) 0.56
Reaction time, familiar blocks [s]
0.78 (±0.21) 0.76 (±0.15) 0.70
Reaction time, novel blocks [s]
1.07 (±0.42) 0.99 (±0.27) 0.56
Whole brain volume [cm
3
]
2038.99 (±168.25) 2016.80 (±205.80) 0.73
Gray Matter*
43.63 (±0.54) 43.78 (±0.93) 0.59
White Matter*
32.76 (±1.11) 32.90 (±0.86) 0.68
CSF*
23.61 (±1.07) 23.32 (±1.41) 0.51
Left Hippocampus*
0.19 (±0.02) 0.20 (±0.01) 0.24
Right Hippocampus*
0.22 (±0.03) 0.23 (±0.02) 0.24
Older group
APOE ε4 carriers
(N = 16)
APOE ε4 non-carriers
(N = 21)
P
Age [years]
65.13 (±8.45) 64.85 (±6.27) 0.92
Sex [Male / Female]
6 / 10 8 / 13 1.00
Education [years]
15.69 (±3.79) 16.66 (±3.54) 0.43
Family history of dementia
3 6 0.70
ACE-r results (max 100)
98.81 (±0.98) 99.29 (±1.27) 0.21
Encoding memory task (max 83)
68.20 (±9.76) 68.90 (±6.57) 0.81
Reaction time, familiar blocks [s]
0.75 (±0.09) 0.72 (±0.11) 0.44
Reaction time, novel blocks [s]
0.99 (±0.15) 0.96 (±0.16) 0.55
Whole brain volume [cm
3
]
1900.07 (±173.27) 1872.54 (±184.07) 0.65
Gray Matter*
41.50 (±1.05) 41.77 (±0.55) 0.35
White Matter*
33.39 (±1.27) 32.95 (±1.18) 0.29
CSF*
25.12 (±1.62) 25.28 (±1.34) 0.74
Left Hippocampus*
0.19 (±0.03) 0.20 (±0.03) 0.37
Right Hippocampus*
0.20 (±0.04) 0.21 (±0.03) 0.35
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Figure 1 Mean FA images with mean FA skeleton used for TBSS (green).
(a) The TBSS results show that FA was significantly decreased in carriers of
the APOE ε4 allele in the younger group (red) (P<0.05). R: right, L: left.
(b) within the older group MD was significantly increased (blue) in APOE ε4-
carriers.
(c) significantly reduced FA (red) in APOE ε4-carriers was found when data
from both age group were pooled.
(d) DR was significantly increased (yellow) in APOE ε4-carriers when data
from both age groups were pooled.
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Figure 2 Mean FA images with mean FA skeleton used for TBSS (green).
(a) FA was significantly higher in the younger compared to the older group
independent of genotype (red) (P<0.05). R: right, L: left.
MD (b), DA (c) and DR (d) were significantly increased in the older group.
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peer-00574005, version 1 - 7 Mar 2011
