Current Topics in Research

American Journal of Alzheimer’s

Disease & Other Dementias®
Family History of Alzheimer’s Disease and 2016, Vol. 31(5) 450-456
ª The Author(s) 2016
Reprints and permission:
Cortical Thickness in Patients With Dementia sagepub.com/journalsPermissions.nav
DOI: 10.1177/1533317516653827
aja.sagepub.com

Steffi Ganske1, Robert Haussmann, MD1, Antonia Gruschwitz, MA1,

Annett Werner, PhD2, Antje Osterrath, PhD1,3, Johanna Baumgaertel1,
Jan Lange, MD1, Katharina L. Donix, MD1, Jennifer Linn, MD2,
and Markus Donix, MD1,3

Abstract
A first-degree family history of Alzheimer’s disease reflects genetic risks for the neurodegenerative disorder. Recent imaging data
suggest localized effects of genetic risks on brain structure in healthy people. It is unknown whether this association can also be
found in patients who already have dementia. Our aim was to investigate whether family history risk modulates regional medial
temporal lobe cortical thickness in patients with Alzheimer’s disease. We performed high-resolution magnetic resonance imaging
and cortical unfolding data analysis on 54 patients and 53 nondemented individuals. A first-degree family history of Alzheimer’s
disease was associated with left hemispheric cortical thinning in the subiculum among patients and controls. The contribution of
Alzheimer’s disease family history to regional brain anatomy changes independent of cognitive impairment may reflect genetic
risks that modulate onset and clinical course of the disease.

Keywords
hippocampus, entorhinal cortex, subiculum, family history of Alzheimer’s disease, MRI, Alzheimer’s disease

Introduction brain changes that can be differentiated from the influence of

Alzheimer’s disease (AD) affects approximately 500 000 new
patients every year in the United States alone, a number that is
expected to double in 2050.1 Aside from early-onset forms of
the neurodegenerative disease due to fully penetrant mutations
in the amyloid precursor protein or presenilin (PSEN1 and
PSEN2) genes, the common late-onset (sporadic) variant has
a complex genetic background and an estimated heritability of
approximately 60% to 80%.2 The e4 allele of the apolipopro-
tein E (APOE4) gene is the most important known genetic risk
factor associated with an allele dose-dependent increased risk
for developing AD and earlier disease onset.3 Genome-wide
association studies have confirmed a number of other suscept-
ibility loci, for example, clusterin (CLU), complement receptor
1 (CR1), bridging integrator 1 (BIN1) or phosphatidylinositol-
binding clathrin assembly protein (PICALM) with small effects
on AD risk, and rare genetic variants, such as phospholipase D3
(PLD3) and Triggering receptor expressed on myeloid cells 2
(TREM2) with moderate to large effects.4 However, there
could be yet undiscovered risk genes of even larger effect size
than APOE4.5 A first-degree family history (FH) of AD can be
conceptualized as a composite risk factor reflecting an individ-
ual risk pattern of known and unknown susceptibility genes,6
associated with a greater risk for developing the disease.7
Across various neuroimaging studies, family history risk has
been shown to be associated with structural and functional
known genetic risk (for review, see Ref. 6).
Using high-resolution magnetic resonance imaging (MRI),
genetic risk factor-associated structural brain changes can already
be found in children and adolescents. Shaw and colleagues showed
a thinner left entorhinal cortex (ERC) in children and young adults
carrying the APOE4 allele.8 This suggests that AD genetic risk
modulates brain structure in medial temporal lobe regions prefer-
entially susceptible to neurodegeneration later in life.9 Neuropatho-
logical AD staging shows that neurofibrillary tangles first occur in
the transentorhinal region before they spread into the subiculum
(SUB) and the hippocampus.9 The AD genetic risk could also
influence structural hemispheric asymmetry.8,10 It may contribute
to the more severe left hemispheric pathology that precedes right
1
Department of Psychiatry, University Hospital Carl Gustav Carus, Technische
Universität Dresden, Dresden, Germany
2
Department of Neuroradiology, University Hospital Carl Gustav Carus,
Technische Universität Dresden, Dresden, Germany
3
DZNE, German Center for Neurodegenerative Diseases, Dresden, Germany
Corresponding Author:
Markus Donix, MD, Department of Psychiatry, University Hospital Carl Gustav
Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Email: markus.donix@uniklinikum-dresden.de
This article was accepted under the editorship of the former Editor-in-Chief,
Carol F. Lippa.
Ganske et al
hemispheric changes by up to 2 years.11 Thompson and col-
leagues revealed that patients with AD show an accelerated gray
matter volume loss in the left hemisphere when compared with
the right hemisphere.11 Pronounced left hemispheric pathology in
AD has been consistently demonstrated in neuropathological
investigations,12 metabolic (fluorodeoxyglucose-positron emis-
sion tomography),13 and structural neuroimaging studies.11,14
Hemispheric asymmetry can be found in healthy people as well,
such as left < right hippocampal volume differences.15 The asym-
metric hemispheric development is mediated by differential gene
expression in both hemispheres,16 and risk genes may contribute
to lateralization effects in neurodegeneration.8,10 Functional
hemispheric specialization, such as the right hippocampus being
predominantly involved in spatial memory, and the critical role of
the left hippocampus for context-dependent episodic memory
illustrate that the course of the clinical symptoms in AD reflects
the asymmetric progression of neurodegenerative changes within
the medial temporal lobes of both hemispheres.17
We previously demonstrated that among cognitively healthy
people, carrying the APOE4 allele is associated with cortical
thinning in the ERC and the SUB.18,19 We also showed that
family history risk explains a greater variance in medial tem-
poral cortical thickness than APOE4 and that the pattern of
cortical thinning associated with both risks could reflect par-
tially different mechanisms contributing to cortical atrophy.20
Patients with cognitive impairment also show volume loss in
the hippocampus and the SUB,21 and cortical thinning in the
ERC and the SUB predicts the clinical course of these
patients.22 However, there are no data available on how genetic
risks influence local medial temporal lobe structure in patients
who already have cognitive impairments and dementia. Stan-
dard MRI data analysis may prevent the detection of subtle risk
factor-associated changes in brain regions already affected by
atrophy. It also remains a research focus whether genetic risks
for AD modulate development and clinical course of the dis-
ease. Whereas APOE4 may be more important for disease
onset rather than disease progression,3,23 the potentially more
complex genetic background reflected in a family history
makes a similar characteristic for this risk factor less likely.
In this study, we used high-resolution MRI and an image
analysis technique that unfolds medial temporal lobe subregions
into a 2-dimensional map24,25 to investigate the influence of AD
family history risk on subregional medial temporal cortical thick-
ness among patients with AD and nondemented controls. We
hypothesized that a family history of AD would be associated
with cortical thinning in the ERC and the SUB, brain regions
affected early in AD development. We also expected that the risk
factor-associated cortical thinning would be primarily left later-
alized and independent of the participants’ cognitive abilities.
Methods
Participants
One hundred seven people participated in this study. They were
recruited through advertisements and through our university hos-
pital’s memory clinic. We selected the participants from a pool of
451
130 individuals who participated in neuropsychological examina-
tions and MRI scanning aimed at investigating AD risk factors.
Twenty-three participants of this sample could not be recruited for
the current study because they did not receive MRI scans. Written
informed consent was obtained; the university’s ethics committee
approved the study. Among the study participants were 53 non-
demented people (mean age 68.9 + 7.0 years) and 54 patients with
AD (mean age 72.3 + 6.6 years). All participants underwent
detailed neuropsychological examinations and MRI brain scans.
We only recruited patients with AD having mild dementia, meet-
ing standard clinical criteria,26 who had the cognitive capacity to
consent. All study participants did not have psychiatric or neuro-
logical disorders other than the cognitive impairment or any sys-
temic disease possibly affecting brain function. Patients with AD
were on stable (>6 months) medication with an acetylcholinester-
ase inhibitor. All patients were right handed and did not receive
any other psychotropic medication. Positive family history risk
was defined as having at least 1 first-degree relative who had been
diagnosed with AD.26 All participants with this risk factor had a
parental family history only. APOE genotype information was
available for all participants with AD.
Procedures
Using a GE Signa HDxt 3-Tesla scanner (General Electric Health
Care, Waukesha, Wisconsin), we obtained high-resolution oblique
coronal T2-weighted fast-spin echo scans (repetition time: 5200
milliseconds; echo time: 105 milliseconds; slice thickness: 3 mm;
spacing: 0 mm; 19 slices; in-plane voxel size: 0.39  0.39 mm;
field of view: 200 mm). Data analysis was performed with a cor-
tical unfolding procedure,24,25 which improves the visibility of the
convoluted medial temporal lobe cortex by flattening the gray
matter volume into 2-dimensional space (Figure 1). We first manu-
ally masked white matter and cerebrospinal fluid on the original
MRI sequence, and then connected layers of gray matter were
grown out using a region-expansion algorithm. The gray matter
volume contains cornu ammonis fields 1 (CA1), CA2,3 and the
dentate gyrus (CA23DG), SUB, ERC, perirhinal cortex, parahip-
pocampal cortex, and the fusiform gyrus. Computational unfolding
of the gray matter volume is based on metric multidimensional
scaling. Boundaries between subregions were delineated on the
original MRI data using histological and MRI atlases27,28 and
mathematically projected to their flat map space coordinates. To
measure cortical thickness, for each gray matter voxel, the distance
to the closest nongray matter voxel is computed. In 2-dimensional
space, for each voxel, the maximum distance value of the corre-
sponding 3-dimensional voxels across all layers is taken and multi-
plied by 2. Thickness in each subregion is calculated by averaging
the thickness of all voxels (for details on cortical unfolding proce-
dures, see Refs. 24,29). In line with our previous studies and MRI
data analysis strategies for cortical thickness in contrast to volu-
metric measures, we report raw data.30 Investigators performing
MRI scanning and cortical unfolding procedures were unaware of
the patients’ clinical and demographic information.
In order to determine the influence of a first-degree family
history of AD on the left and right hemispheric entorhinal and
452 American Journal of Alzheimer’s Disease & Other Dementias® 31(5)

Figure 1. Cortical unfolding acquired on oblique coronal MRI scans (A) perpendicular to the long axis of the hippocampus (B). After manual
segmentation of white matter and CSF, the gray matter volume is computationally unfolded and flattened based on metric multidimensional
scaling (C, right hemispheric flat map). Boundaries between the subregions are applied to the high-resolution MRI sequence (B) and mathe-
matically projected to the 2-dimensional space. CA23DG indicates cornu ammonis fields 2,3 and dentate gyrus (the anterior part of the cornu
ammonis fields and dentate gyrus [AntCADG] is part of the CA23DG region); CA1, CA field 1; CSF, cerebrospinal fluid; ERC, entorhinal cortex;
FUS, fusiform gyrus (fusiform boundary depicts the medial fusiform vertex, dotted line); MRI, magnetic resonance imaging; PHC, parahippo-
campal cortex; PRC, perirhinal cortex; SUB, subiculum.

subicular cortical thickness, we estimated mixed general linear
models with subregions as the dependent variables, cognitive
status (nondemented/demented) and family history risk (yes/
no) as between-group factors, and age and Mini Mental State
Examination (MMSE) score as covariates. We also investi-
gated a possible interaction between cognitive status and fam-
ily history risk on cortical thickness. After we established
significance with the multivariate F tests, we conducted post
hoc univariate tests to determine the influence of family history
risk on regional cortical thickness. Gender and family history
distribution were compared with w2 tests. Statistical analyses
used a significance level of P < .05.
Results
Nondemented individuals and patients with AD did not signif-
icantly differ in educational status or gender distribution.
Patients with dementia were significantly older; therefore, we
modeled age as a covariate in all analyses. We also used the
MMSE score as a covariate in all analyses in order to account
for possible MMSE-related effects given the difference in
MMSE distribution between patients and controls. However,
the family history risk groups did not significantly differ in
MMSE scores within patients and controls (controls FH:
28.9, FHþ: 28.8, patients FH: 22.7, FHþ: 22.9).
Although the groups did not significantly differ in this
characteristic, there was an expected trend for a higher fre-
quency of family history risk among patients with AD when
compared with controls (Table 1), resulting in an unbalanced
risk factor distribution. Therefore, we further investigated a
possible factor interaction in the general linear model by
determining the type of interaction. We found an ordinal
interaction type that enables us to interpret the main effects
in the way presented here.
When considering right and left (average) cortical thickness,
the mixed general linear model yielded significant effects for
cognitive status (demented/nondemented; F ¼ 16.4, df ¼ 2.98,
P < .001) and family history risk (yes/no) (F ¼ 3.81, df ¼ 2.98,
Ganske et al 453

Table 1. Demographic Characteristics and Neuropsychological Scores.

Characteristics and Measures CTL SD AD SD Significance (P Value)a

N 54 53
Age (years) 68.9 +7.0 72.3 +6.6 .01
Female sex (%) 45.3 50.0 .63
Education (years) 14.3 +2.6 13.4 +2.5 .06
FHþ (%) 24.5 40.7 .07
MMSE (score range 0-30) 28.8 +1.2 22.8 +5.1 <.001
Abbreviations: AD, Alzheimer’s disease; CTL, nondemented control participants; FHþ, first-degree family history of Alzheimer’s disease; MMSE, Mini Mental State
Examination; SD, standard deviation.
a 2
w tests for gender and family history risk distribution.

Figure 2. Right and left hemispheric cortical thickness is shown for the subiculum (SUB) and entorhinal cortex (ERC). As expected, patients
with Alzheimer’s disease (DAT) showed a thinner cortex in both regions compared with controls (CTL) in the right and left hemisphere. A
positive first-degree family history of Alzheimer’s disease (FHþ) was associated with a thinner subiculum in the left hemisphere independent of
the participants’ cognitive abilities.

P ¼ .026). There was no significant interaction between cog-
nitive status and family history risk. Patients with AD had a
significantly thinner ERC than controls (AD: 2.23 + 0.13 mm,
controls: 2.55 + 0.22 mm, P < .001) and a thinner SUB (AD:
1.90 + 0.15 mm, controls: 2.08 + 0.14 mm, P ¼ .001).
Patients with a positive first-degree family history of AD
showed a significantly thinner SUB than participants without
this risk factor (FHþ: 1.92 + 0.13 mm, controls: 2.03 + 0.18
mm, P ¼ .008), whereas entorhinal cortical thickness was not
significantly different.
When investigating both hemispheres separately (Figure 2),
dementia was associated with a thinner ERC and SUB in both
hemispheres (right hemisphere: F ¼ 25.08, df ¼ 2.98, P < .001,
left hemisphere: F ¼ 7.97, df ¼ 2,98, P ¼ .001). Positive AD
family history was associated with a thinner SUB only in the
left hemisphere (F ¼ 4.4, df ¼ 2,98, P ¼ .015). Entorhinal
cortical thickness did not vary due to family history status in
both hemispheres.
We additionally investigated whether the APOE genotype
would influence cortical thickness in the entorhinal region and
the SUB among patients with AD. Although we found a trend
in the left hemisphere toward entorhinal cortical thinning, there
was no significant association of APOE genotype and cortical
thickness in patients with dementia. Cortical thinning in the
SUB was not explained by the APOE genotype.
Discussion
In this study, we show that a positive first-degree family history
of AD is associated with cortical thinning in the left hemi-
spheric SUB. The effect was independent of the patients’ cog-
nitive impairments and could be detected in individuals with
454
AD as well as in control participants. Entorhinal cortical thick-
ness did not vary due to the presence of the family history risk
factor.
We previously demonstrated how genetic risks modulate
entorhinal and subicular cortical thickness in cognitively
healthy people.18,19 An additive effect for family history risk
and the APOE4 allele was detectable in the SUB in contrast to
the ERC, where both risks did not influence cortical thickness
more than either risk factor alone.20 In this study, we addition-
ally investigated a possible influence of APOE4 genetic risk on
entorhinal and subicular cortical thickness in patients with AD.
Although we found a trend for entorhinal rather than subicular
cortical thinning due to the risk allele, this association was not
significant. This finding is in line with the hypothesis that
APOE4 may preferentially influence the onset rather than the
clinical course of AD3,23; however, the impact of APOE4 allele
dose on disease progression may become more obvious using
nonlinear statistical models.31 We show that family history-
associated effects are still detectable among patients with
AD. The possibly more complex genetic background that con-
tributes to family history risk could involve risk genes that
modulate brain structure and function through many different
mechanisms across preclinical and clinical stages of AD devel-
opment and progression.
Hippocampal shape changes are most pronounced in CA1
and the SUB among patients with AD.32 Scher and colleagues
highlight localized hippocampal atrophy in the lateral portion
of the left hippocampus that includes the SUB in AD when
compared with vascular dementia.33 Recent data from an
ultrahigh-field MRI postmortem study suggest microscopic
iron and activated microglia specifically in the SUB of patients
with AD, consistent with spreading neurodegeneration along
entorhinal projections to the hippocampus.34,35 It shows that
innovative MRI techniques contribute to our understanding of
AD-associated pathology and its subregional effects on medial
temporal lobe integrity. Recent animal data show that the SUB
is the earliest hippocampal region showing severe neuronal loss
in a mice model of AD36 and that subicular neuron damage
could be related to AD through neuroinflammatory pathways.37
In AD, the neurofibrillary tangle load correlates with cog-
nitive impairment.38 Neuropathological data suggest that neu-
rofibrillary tangle formation could be accelerated in the SUB
in contrast to the entorhinal region,39 an effect that was not
associated with the APOE4 allele.39 To date, the possible
association of AD susceptibility genes other than APOE4 with
brain structure has been rarely investigated. Bralten and col-
leagues did not find genotype-related local gray matter vol-
ume differences in healthy people for CLU and PICALM but
showed smaller ERC volumes among CR1 risk allele car-
riers.40 Others found an association of PICALM with hippo-
campal volume.41 A rare and dysfunctional variant of the
TREM2 gene, encoding a protein with anti-inflammatory
characteristics that is highly expressed in the hippocampus,
increases the risk for developing late-onset AD to a magnitude
possibly comparable with APOE440; however, brain imaging
data are not yet available.
American Journal of Alzheimer’s Disease & Other Dementias® 31(5)
It is likely that many risk alleles ultimately influence neu-
ronal damage and atrophy in AD; however, measuring global
cortical or medial temporal lobe atrophy42 may not be suffi-
cient to reveal the regional effects of genetic risks that could be
additive with or independent of APOE4-associated structural
brain changes.20 Furthermore, in MRI studies, subregional
analyses may be necessary to detect the differences in risk-
related brain structure changes across risk factors.6,20
Investigating family history risk-associated changes in radi-
ological brain anatomy cannot be used to differentiate the indi-
vidual effects of risk genes that could vary among individuals.
Other study limitations include that nongenetic risk factors that
are passed on through generations could also be part of the
family history risk factor.6,43 In our participant sample, APOE
information was only available for patients with dementia, so
we cannot make direct inferences about the differences or simi-
larities of APOE- and family history risk-associated effects
among control participants. However, we previously demon-
strated the influence of both risks on brain structure in healthy
individuals.18-20 Finally, healthy relatives of study participants
could develop AD in the future, and it cannot be determined
clinically whether APOE4 and/or other risk genes contributed
to the family history among individual participants with this
risk factor.
In summary, we show an association of a first-degree family
history of AD with subicular cortical thinning in the left hemi-
sphere among patients with AD and nondemented individuals.
Our data contribute to the idea that genetic risks for AD mod-
ulate local brain structure in key regions susceptible to neuro-
pathological changes. Localization and lateralization patterns
of such effects reflect the characteristic clinical impairments
and their time course. Future research will be necessary to
determine the influence and interplay of individual risk genes
on brain anatomy and function. Until then, it is important to
model the family history factor in MRI investigations of people
at risk for cognitive decline and also in patients who already
have AD.
Authors’ Note
Steffi Ganske and Robert Haussmann contributed equally to the
manuscript.
Acknowledgments
The authors would like to thank Susan Bookheimer, Department of
Psychiatry and Biobehavioral Sciences, David Geffen School of Med-
icine at UCLA, for support and assistance with cortical unfolding. The
authors also thank Cathrin Sauer for her suggestions on the statistical
models.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
Linn has received research support from B. Braun Stiftung,
Ganske et al
Friedrich-Baur-Stiftung, and the Förderprogram für Forschung
und Lehre and received travel expenses and/or honoria for edu-
cational lectures from Bayer Healthcare, Phillips Healthcare, and
Bracco. Donix has received research support from the Roland
Ernst Stiftung and a consulting fee from Trommsdorff. The study
was funded by a Young Investigator Grant (MeDDrive 60.338) of
the TU Dresden to Markus Donix.
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