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: jeongsk@jbnu.ac.kr

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

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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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