ORIGINAL COMMUNICATION
The effect of an APOE polymorphism on cognitive functiondepends on age
Min-Ho Shin • Sun-Seog Kweon • Jin-Su Choi • Young-Hoon Lee •
Hae-Sung Nam • Kyeong-Soo Park • Hee N. Kim • Hye-Rim Song •
Byeong C. Kim • Seong-Min Choi • Sun-Young Oh • Seul-Ki Jeong
Received: 19 July 2013 / Revised: 11 October 2013 / Accepted: 11 October 2013 / Published online: 22 October 2013
� Springer-Verlag Berlin Heidelberg 2013
Abstract It remains controversial whether APOE E4
polymorphism is related to cognitive function in general
population. We aimed to evaluate an association between
the APOE E4 genotype and cognitive function, and whe-
ther this association may differ by age. Cognitive function
was assessed using the Korean version of modified Mini-
Mental State Examination (K-mMMSE) in 10,371 Koreans
aged 45–74 years in Namwon City. According to the
APOE E4 status, all participants were classified as non-
carriers, heterozygotes, or homozygotes. Multiple linear
and logistic regression models were used to evaluate the
association between APOE genotypes and cognition. The
frequency of APOE genotypes in the study population was
0.4, 10.1, 1.1, 72.9, 14.7 and 0.8 % for E2E2, E2E3, E2E4,
E3E3, E3E4, and E4E4, respectively. Compared to the
APOE E4 non-carriers, the heterozygotes and homozygotes
showed 1.3 and 7.3 % lower K-mMMSE scores at 65–74
years and 0.8 and 4.6 % higher scores at 45–55 years,
respectively. Educational attainment modified the effect of
APOE E4 on cognitive function in the 45–54 age group
(p for interaction =0.003), showing that the E4 carriers with
no-formal education showed significantly higher cognitive
function than those with formal education. The present
study demonstrates that the effect of APOE E4 on cogni-
tive function depends on age and education.
Keywords Age � Apolipoprotein E � Cognition �Genetic polymorphism � K-mMMSE
Introduction
Recently over a dozen potential Alzheimer’s disease sus-
ceptibility genes have been reported [1], and one of the
M.-H. Shin � S.-S. Kweon � J.-S. Choi � H.-R. Song
Department of Preventive Medicine, Chonnam National
University Medical School, Gwangju, Republic of Korea
S.-S. Kweon
Jeonnam Regional Cancer Center, Hwasun Hospital,
Chonnam National University Hwasun Hospital, Hwasun,
Republic of Korea
Y.-H. Lee
Department of Preventive Medicine & Institute of Wonkwang
Medical Science, Wonkwang University School of Medicine,
Iksan, Republic of Korea
H.-S. Nam
Department of Preventive Medicine, Chungnam National
University Medical School, Daejeon, Republic of Korea
K.-S. Park
Department of Preventive Medicine, Seonam University College
of Medicine, Namwon, Republic of Korea
H. N. Kim
Genome Research Center for Hematopoietic Diseases,
Chonnam National University Hwasun Hospital, Hwasun,
Republic of Korea
B. C. Kim � S.-M. Choi
Department of Neurology, Chonnam National University
Medical School, Gwangju, Republic of Korea
S.-Y. Oh � S.-K. Jeong (&)
Department of Neurology, Research Institute of Clinical
Medicine Chonbuk National University, Biomedical Research
Institute of Chonbuk National University Hospital, San 2-20,
Geumam-dong, Deokjin-gu, Jeonju 561-180, Republic of Korea
e-mail: [email protected]
123
J Neurol (2014) 261:66–72
DOI 10.1007/s00415-013-7157-y
firmly established genetic susceptibility (or risk) factor for
familial or sporadic Alzheimer’s disease is the E4 allele of
APOE (APOE E4) [2]. Apolipoprotein E (APOE; gene,
apoE; protein) is a protein synthesized by astrocytes and
plays an important role in cholesterol metabolism.
Although APOE E4 has been known to be a risk factor for
the development of Alzheimer’s disease in the elderly, it
remains controversial whether the APOE polymorphism is
related to cognitive function or cognitive decline in the
general population. Some previous studies have shown that
APOE E4 has an early effect on cognitive function in the
selected populations with relatively high frequencies of the
APOE E4 allele [3, 4], and in subjects with relatively high
proportions of albuminuria [5]. However, no previous study
has reported the relationships between age, APOE E4 status,
and cognition in the general population, especially in Asians.
In the present study, we hypothesized that APOE E4
may be associated with poorer cognitive performance and
the association between the APOE polymorphism and
cognition may differ by age. To determine this association,
we examined cognitive function in a general Korean pop-
ulation aged 45–74 years. Using the data, we analyzed
whether the association between the APOE polymorphism
and cognition was significant, and whether the association
was modified by age.
Subjects and methods
Study population
The Namwon Study is an ongoing prospective study
designed to investigate the prevalence, incidence, and risk
factors for chronic diseases in a rural population. Details of
study participants and measurements have been published
previously [6]. A total of 10,667 participants (4,201 men
and 6,466 women) were recruited in the baseline survey
between January 2004 and February 2007 in Namwon city
of Jeonbuk province in South Korea; 296 participants were
excluded because of missing cognition, genotype, or edu-
cation data. Following these exclusions, data on 10,371
participants (4,066 men, 6,305 women) were included in
the present analyses. This study was conducted in accor-
dance with the Declaration of Helsinki guidelines. The
study protocol was approved by the Institutional Review
Boards of Chonnam National University Hospital and
Chonbuk National University Hospital independently, and
informed consent was obtained from each participant.
APOE genotyping
Genomic DNA was extracted from peripheral blood with
an AccuPrep Genomic DNA Extraction Kit (Bioneer,
Seoul, Korea) or a QIAamp DNA Mini Kit (Qiagen Inc.,
Chatsworth, CA) according to the manufacturers’ protocol.
APOE genotypes were determined as described by Hixson
and Vernier, with slight modification [7]. Our APOE
genotyping method has been reported previously [8].
Measurement of cognitive function
An apparently healthy population with no limitation of
motion and behavioral problem were screened for cogni-
tive function. Cognitive function was measured using the
Korean version of modified Mini-Mental State Examina-
tion (K-mMMSE), which was validated and proven as
having a finer discrimination of cognitive impairment and
dementia in a Korean elderly population [9]. The
K-mMMSE is scored on a 100-point scale, with higher
scores indicating greater cognition. From the global cog-
nitive measures, scores of cognitive domains including
attention, orientation, memory (registration, immediate and
delayed recall, and remote memory), language, frontal
executive function, and visuospatial functions were
extracted and used for statistical analyses. A project neu-
rologist (SKJ) supervised the examinations, and two more
neurologists (BCK and SMC) independently administered
the final scoring of the K-mMMSE. Cognitive impairment
was defined as scoring below the 25th percentile according
to age, sex, and educational attainments. Interquartile
ranges of K-mMMSE scores in men and women were
74–89 and 59–81, respectively (all scores ignoring age and
education), as reported previously [10].
Statistical analysis
Data are presented as mean ± standard deviation (SD) or
percentage for categorical variables. Analysis of variance
and Pearson’s chi-square test were used to compare baseline
characteristics across APOE genotypes. Participants were
classified as APOE E4 non-carriers (E2/E2, E3/E3 and E2/
E3), APOE E4 heterozygotes (E2/E4 and E3/E4) or APOE
E4 homozygotes (E4/E4). Educational attainment was cat-
egorized as follows: no school, elementary school, middle
school, high school or higher education, but for interaction
analysis the educational attainment was dichotomized into
formal and no-formal education. Because the effect of the
APOE genotype differed by age, age-stratified analysis was
performed. Participants were categorized by age in the
following groups: 45–54, 55–64, and 65–74 years. How-
ever, we did not analyze the data separately by sex because
there was no significant interaction between sex and APOE
E4 status on cognitive function or cognitive impairment.
Multiple linear regression models were used to evaluate the
association between APOE genotypes and cognitive func-
tion. A logistic regression model was used to evaluate the
J Neurol (2014) 261:66–72 67
123
association between APOE genotypes and cognitive
impairment. In the multivariate models, age, sex, and edu-
cational levels were adjusted. Hardy–Weinberg equilibrium
was tested by use of a v2 goodness of fit test. Statistical
analyses were performed using SPSS version 20.0 (IBM
SPSS, Chicago, IL, USA). Statistical significance was set at
p \ 0.05.
Results
The participant characteristics at baseline are presented in
(Table 1). Men were slightly but significantly older than
women (mean ± SD, 62.2 ± 7.6 years for men and
61.2 ± 7.9 years for women, p \ 0.001), and the age
group 45–54 was slightly greater in women. Men had a
higher level of education than women. Men had a higher
K-mMMSE than women (mean difference 9.6, 95 % con-
fidence intervals 9.0–10.1). This difference was markedly
attenuated to 3.8 (95 % CI 3.3–4.3) but remained signifi-
cant, after age and education levels were adjusted (data not
shown). The APOE genotype frequencies were consistent
with Hardy–Weinberg equilibrium (p = 0.92) and not
significantly different between men and women. The fre-
quency of APOE genotypes of total study population was
0.4, 10.1, 1.1, 72.9, 14.7 and 0.8 % for E2E2, E2E3, E2E4,
E3E3, E3E4, and E4E4, respectively. The allelic frequen-
cies of APOE E2, E3, and E4 were 6.0, 85.3, and 8.7 %,
respectively.
APOE E4 (E3/E4 and E4/E4) group showed signifi-
cantly lower cognitive function than APOE E3 (E3/E3)
group, but there was no significant difference for the
K-mMMSE scores between APOE E2 (E2/E2 and E2/E3)
and APOE E3 (E3/E3) groups (data not shown). The crude
associations of APOE E4 status with cognitive function are
depicted in (Fig. 1), and multivariate associations are
shown in (Table 2). There was a significant interaction
between age and APOE E4 status on cognitive function
(p for interaction = 0.006). The stratified analyses by age
group (45–54, 55–64, 65–74 years) showed that there was
a significant difference in the K-mMMSE scores between
APOE E4 status in the age groups 55–64 years and
65–74 years, but not in the age group 45–54 years. The
variance of the K-mMMSE scores explained by the APOE
E4 status after adjustment for covariates was 0.4 and 0.2 %
in the 55–64 and 65–74 age groups, respectively. Educa-
tional attainment modified the effect of APOE E4 on
cognitive function in the 45–54 age group (p for interaction
=0.003), but not in the other age groups. In the 45–54 age
group, APOE E4 carrier showed significantly higher
K-mMMSE scores in the no-formal education group, but
not in the formal education group (Fig. 2).
The association of APOE E4 status with cognitive
impairment (below the 25th percentile) is shown in
(Table 3). There was a significant interaction between age
and APOE E4 status on cognitive impairment (p for
interaction =0.047). In the 65–74 age group, E4 homozy-
gotes had a higher risk for cognitive impairment
(OR = 2.38, 95 % CI = 1.13–4.98), but not E4 heterozy-
gotes (OR = 1.15, 95 % CI = 0.94–1.40).
The association between APOE E4 status and the cog-
nitive domain scores is shown in (Table 4). In the 55–64
Table 1 Characteristics of the study participants by sex
Men Women p
N 4,066 6,305
Age (years) 62.2 ± 7.6 61.2 ± 7.9 \0.001
Age group \0.001
45–54 860 (19.8) 1,541 (24.4)
55–64 1,522 (37.4) 2,397 (38.0)
65–74 1,738 (42.7) 2,367 (37.5)
Educational level
No 603 (14.8) 3,013 (47.8) \0.001
Primary school 1,843 (45.3) 2,332 (37.0)
Middle school 749 (18.4) 580 (9.2)
High school 871 (21.4) 380 (6.0)
APOE genotype 0.380
E2E2 17 (0.4) 22 (0.3)
E2E3 413 (10.2) 635 (10.1)
E2E4 33 (0.8) 77 (1.2)
E3E3 2,984 (73.4) 4,574 (72.5)
E3E4 583 (14.3) 945 (15.0)
E4E4 36 (0.9) 52 (0.8)
K-mMMSE score 82.9 ± 11.6 73.3 ± 15.7 \0.001
Values are mean ± SD or number (percentage)
K-mMMSE Korean version of modified mini-mental state
examination
60.0
65.0
70.0
75.0
80.0
85.0
90.0
95.0
45-54 55-64 65-74
Non-carrierHeterozygotesHomozygotes
Age, years
K-m
MM
SE
, sco
re
Fig. 1 Line chart for the K-mMMSE scores and age distributions
according to the APOE E4 status (non-carriers, heterozygotes, and
homozygotes)
68 J Neurol (2014) 261:66–72
123
age group, compared with E4 non-carriers, E4 heterozy-
gotes had lower scores in attention, memory, visuospatial,
and language functions, but not in orientation, abstract
thinking, and frontal executive function. In the 65–74 age
group, compared with the non-carriers, E4 homozygotes
showed lower score in all domains but only orientation was
Table 2 Association of APOE E4 allele status with cognitive function (the K-mMMSE scores) according to age group
APOE E4 allele 45–54 55–64 65–74
N Mean ± SE p* N Mean ± SE p* N Mean ± SE p*
Non-carrier 1967 83.4 ± 0.2 3240 81.1 ± 0.2 3438 77.2 ± 0.3
Heterozygote (HTZ) 363 84.1 ± 0.5 0.214 638 79.2 ± 0.4 \0.001 637 76.2 ± 0.5 0.053
Homozygote (HMZ) 17 87.3 ± 2.3 0.085 41 80.8 ± 1.7 0.868 30 71.6 ± 2.2 0.042
Carrier (HTZ ? HMZ) 380 84.2 ± 0.5 0.121 679 79.3 ± 0.4 \0.001 667 75.9 ± 0.5 0.018
p for between group 0.112 \0.001 0.007
p for trend 0.070 \0.001 0.006
Partial R2a 0.002 0.004 0.002
Data are presented as mean ± standard error
Adjusted for age, sex and educational level* p values were determined by pairwise comparison with non-carriersa Variance explained by APOE genotype after adjustment for covariates
68.8
86.9
67.2
83.6
62.7
81.1
74.9
87.0
64.9
82.3
61.4
80.1
50
60
70
80
90
100
45-54 years 55-64 years 65-74 yearsEducation+
E4 non-carrier E4 carrier
Education-Education- Education+ Education- Education+
K-m
MM
SE, s
core
p for interaction = 0.003 p for interaction = 0.352 p for interaction = 0.785
p = 0.008 p = 0.099
p = 0.724
p = 0.045
p = 0.020
p = 0.105
Fig. 2 Interaction of education
and APOE E4 allele status on
cognitive function according to
age group. Data was adjusted
for age and sex. Education
status modified the effect of
APOE E4 on cognitive function
in the 45–54 age group (p for
interaction =0.003), but not in
the other age groups
Table 3 Association of APOE E4 allele status with cognitive impairment according to age group
APOE E4 allele 45–54 55–64 65–74
Affected/unaffected OR (95 % CI) Affected/unaffected OR (95 % CI) Affected/unaffected OR (95 % CI)
Non-carrier 470/1497 1.00 (reference) 737/2503 1.00 (reference) 794/2644 1.00 (reference)
Heterozygote 76/287 0.83 (0.63–1.09) 182/456 1.34 (1.14–1.67) 163/474 1.15 (0.94–1.40)
Homozygote 1/16 0.19 (0.03–1.48) 9/32 0.94 (0.45–1.99) 12/18 2.38 (1.13–4.98)
Carrier 77/303 0.79 (0.60–1.05) 191/488 1.35 (1.12–1.63) 175/492 1.19 (0.98–1.44)
p for trend 0.056 0.005 0.030
Adjusted for age, sex and educational level
Cognitive impairment was defined as scoring below the 25th percentile according to age, sex, and educational attainments
J Neurol (2014) 261:66–72 69
123
significant. In the 45–54 or 55–64 age group, all of the
cognitive domains showed higher scores in the APOE E4
carriers especially in the homozygotes, but did not reach
statistical significance.
Discussion
The present study in a community dwelling population
showed that APOE E4 carriers had lower cognitive func-
tion than the E4 non-carriers in the elderly subpopulation,
and age modified the effect of the APOE genotype on
cognitive function. Compared to the APOE E4 non-carri-
ers, the heterozygote group showed 2.3 % lower
K-mMMSE scores at 55–64 years and 1.3 % lower scores
at 65–74 years, while the homozygote group showed no
significant difference of scores at 55–64 years but 7.3 %
lower scores at 65–74 years. Interestingly, the APOE E4
carriers with no formal education showed significantly
higher K-mMMSE scores than the E4 non-carriers at 45–55
years. The present study demonstrated the interactive effect
of age on APOE genotype and cognitive function while
showing the positive effect of APOE E4 on cognition in
young adults (with no formal education) and the negative
effect in the elderly.
APOE E4 allele has been reported to be associated with
dementia [2, 11], poorer memory performance in healthy
aging [12], and more rapid cognitive decline [13] espe-
cially, in the group with high grade education [14],
although the evidence for disease progression is still
insufficient [15]. The effects of the APOE genotype on the
increased risk of Alzheimer’s disease are likely to be
mediated by differential effects of apoE4 on amyloid-baccumulation in the brain [16, 17]. APOE E4 status was
significantly associated with lower cerebrospinal fluid b-
amyloid1–42 levels [18], increased synapse loss [19], and
functional network disruption in patients with Alzheimer’s
disease [20]. Even in cognitively normal elderly individu-
als, APOE E4 status was significantly associated with
increased cerebral amyloid-b deposition [21].
However, many previous studies among young adults
have shown beneficial effects of APOE E4 on cognition. In
young APOE E4 carriers, behavioral advantages with a
wider field of attention [22], better neuropsychological
performance after traumatic brain injury [23], an economic
use of memory-related neural resources [24], better per-
formance intelligence quotient and N100 amplitudes [25]
have been reported.
It suggested that the effects of APOE E4 on cognition
might be better understood in terms of time, from early
adulthood, as the previous and present studies demon-
strated [26]. The initial pathological feature of Alzheimer’s
disease, amyloid-b deposition in the brain, is estimated toTa
ble
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70 J Neurol (2014) 261:66–72
123
begin years prior to the substantial neurodegeneration that
shows clinical signs and symptoms of cognitive decline
[27]. The time interval between amyloid-b deposition and
clinical signs of cognitive dysfunction might be affected by
APOE E4 status, but the interactive effect of age on the
association between APOE E4 and cognition has not been
shown in the general population [5, 28].
Two previous studies in which APOE E4 was enriched
up to 21.1 % [3] and 24.3 % [4] have shown an age
interaction, but no evidence of better cognitive perfor-
mance in young APOE E4 carriers was noted. The allelic
frequency of APOE E4 in the present Korean population
was 8.7 %, and which was similar to the previous reports
among Chinese and Japanese samples [29, 30]. In the
present study, APOE E4 carriers with no-formal education
showed significantly higher cognitive performance in the
45–54 age group, and lower scores of cognition after age
65. The diverse effects of APOE E4 on cognitive function
depended on age and education. APOE E4 is thought to be
involved in antagonistic pleiotropy [31], however, the
present study does not provide sufficient evidence to sub-
stantiate this theory and thus, it is still unclear [22, 28].
The overall effect of APOE E4 status on the variance of
cognitive function was quite small in the present study
(0.2–0.4 %), which is consistent with previous studies [3–
5]. Therefore, it is important for a study to have sufficient
power to detect these small effects. The present study was
performed in a large sample population with a wide range
of age distribution (45–74 years), which were essential to
reveal the age effect on APOE genotypes and cognition.
More importantly, there were substantially high propor-
tions of participants with low educational attainment
(34.9 % for no formal educational attainment). The edu-
cational heterogeneity of the population was important in
revealing the genuine effect of APOE E4 on cognition,
depicted as in Fig. 2, because evenly distributed high
educational attainments might cover the small effect of the
gene.
Our study has some limitations. First, the cross-sectional
study could not reveal the causal relations between APOE
genotypes and cognitive function. Second, cognitive func-
tion was measured with only one global cognitive measure,
the K-mMMSE. However, detailed neuropsychological
examinations including various cognitive domains needs
more time and concentration for both participants and
examiners to perform, and that kind of study design limits
the numbers of participant, which subsequently limits the
statistical power. Thus, the present topic, the association
between APOE E4 and cognitive function, which had a low
to modest effect size, should be analyzed using a study
designed to balance the effect size and total participants.
Third, compared to the elderly population, smaller numbers
of young adults aged 45–54 were included.
In conclusion, the present study in the Korean general
population demonstrated that the effect of the APOE E4
allele on cognitive function depends on age; APOE E4 is
significantly associated with lower cognitive function in
the elderly, whereas APOE E4 is associated with higher
cognition in the young adult population with no formal
education. Our results suggest that the APOE genotype
may have a positive effect until late adulthood, and then
negatively influence cognitive function in the elderly.
Acknowledgments This paper was supported by the Research
Institute of Clinical Medicine, Chonbuk National University, and the
Biomedical Research Institute of Chonbuk National University
Hospital.
Conflicts of interest Nothing to declare.
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