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Neurobiology of Aging 31 (2010) 1831–1833
The apolipoprotein E gene and its age-specific
effects on cognitive function
Fan Liua,1, Luba M. Pardoa,1, Maaike Schuura,b, Pascual Sanchez-Juana,c,d, Aaron Isaacsa,
Kristel Sleegersa,e, Ingrid de Koningb, Irina V. Zorkoltsevaf, Tatiana I. Axenovichf,
Jacqueline C.M. Wittemana, A. Cecile J.W. Janssensa,g, John C. van Swietenb,
Yurii S. Aulchenkoa,f, Ben A. Oostraa, Cornelia M. van Duijna,∗
aDepartments of Epidemiology & Biostatistics and Clinical Genetics, Erasmus University Medical Center Rotterdam, The Netherlands
bDepartment of Neurology, Erasmus University Medical Center Rotterdam, The Netherlands
cInstituto de Formación e Investigación Marqués de Valdecilla, Fundación Marqués de Valdecilla, Santander, Spain
dCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain
eNeurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerpen, Belgium
fInstitute of Cytology & Genetics SD RAS, Novosibirsk, Russia
gDepartment of Public Health, Erasmus University Medical Center Rotterdam, The Netherlands
Received 9 April 2008; received in revised form 16 September 2008; accepted 24 September 2008
Available online 11 November 2008
The E4 allele of the apolipoprotein E gene (APOE) is a well-established determinant of Alzheimer’s disease but its relation to cognitive
function is much less understood. We studied the age-specific effects of the APOE*E4 allele on cognitive function and cardiovascular risk
factors in 2208 related individuals. APOE*E4 allele was significantly associated with reduced test scores for Adult Verbal Learning Test,
particularly on the memory and learning sub domains, in persons older than 50 years of age. The effect of APOE*E4 was independent of the
effect of APOE*E4 on vascular risk factors and most pronounced on learning ability. Our findings suggest that APOE*E4 has an effect on
cognitive function predominantly in the elderly, independent of vascular risk factors.
Crown Copyright © 2008 Published by Elsevier Inc. All rights reserved.
Keywords: Cognitive function; APOE; Age; Alzheimer’s disease; Genetic analysis
The epsilon4 allele of the apolipoprotein E gene
(APOE*E4) is the most well-known genetic risk factor for
Alzheimer’s disease (AD) but its effect of cognitive func-
tion is less well understood. An extensive meta-analysis of
studies conducted in 1993–2004 showed evidence for a role
of APOE*E4 also in cognitive function in non-demented
∗Corresponding author at: Genetic Epidemiology Unit, Department of
Epidemiology & Biostatistics, Erasmus Medical Center Rotterdam, Dr.
Molewaterplein 50, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Tel.: +31 10 7043394; fax: +31 10 7089406.
E-mail address: firstname.lastname@example.org (C.M. van Duijn).
1Both authors contributed equally.
analysis focused on people over 50 years of age. APOE*E4
has also an established effect on cardiovascular factors, such
potentially be an intermediate feature explaining part of its
effect on cognition. We aimed to investigate (1) the effect
of APOE*E4 on cognition early- and late in life and (2)
whether the APOE*E4 effect is dependent on its effect on
The current report is based on 2208 participants from
Erasmus Rucphen Family (ERF) cohort (see supplementary
0197-4580/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Inc. All rights reserved.
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F. Liu et al. / Neurobiology of Aging 31 (2010) 1831–1833
material for details). Neuropsychological test battery is
described in detail in the supplements and included the
Dutch version of the Auditory Verbal Learning Test (AVLT),
the Trail Making Test (TMT), the Stroop colour–word test,
the verbal fluency test and the block design subtest of
the Weschler Adult Intelligence Scale (WAIS), and the
Dutch Adult Reading Test (DART). Compound scores were
computed for memory, executive function, and global cog-
nition (supplementary Table 1). Cardiovascular risk factors
included serum total cholesterol, high-density lipoprotein
(HDL) cholesterol, triglycerides, systolic and diastolic blood
The data collection of lipids and other measurements are
described in detail in supplementary material. APOE geno-
typing and calculation of inbreeding coefficients have been
described previously in detail (Isaacs et al., 2007). APOE
genotypes were coded as 0, 1, or 2 number of E4 alleles.
The effect of the E4 allele on cognition and vascular risk
factors was estimated using the variable screening analysis
under a polygenic model using the SOLAR-4.1.0 (Almasy
and Blangero, 1998). Models were adjusted for age, sex,
education, inbreeding, DART score, and cardiovascular risk
factors (total cholesterol, triglycerides, IMT, and systolic
and diastolic blood pressure). Subjects were stratified into
two groups by age of 50 years according to the previous
meta-analysis (Small et al., 2004). Multiplicative interaction
between genotype and age was examined. Cognition scores
were smoothed across age using locally weighted regression
(LOESS), implemented in the software package SigmaPlot
version 8.02 (Dagum and Luati, 2001).
The average age was 49.1 (14.1) years, 21.1% carried
the E4 allele. We excluded 65 individuals who were illit-
erate, blind, deaf, retarded or who reported having a brain
tumour, stroke or severe brain damage. APOE*E4 was sig-
nificantly associated with serum cholesterol, triglycerides,
and HDL in both age groups (Table 1). APOE*E4 was
also significantly associated with poorer memory perfor-
mance in those over 50 years of age (AVLT short-term
memory, P=0.01; AVLT learning, P=0.001; AVLT delayed
recall, P=0.01; and memory compound score, P=0.001).
Supplementary Table 2 shows the relation of the cardio-
vascular factors to cognitive functioning. IMT and systolic
tiple cognitive domains (P<0.0001). However, adjusting for
cardiovascular factors had little influence on the effects on
cognitive function (Table 1). Fig. 1 shows the effect of the
APOE genotype on AVLT learning by age. The figure sug-
gests the APOE effect starts around age 40 years for those
homozygous for APOE*E4 and by age 60 years for those
heterozygous (Fig. 1). In younger subjects (≤50 years), none
of the tests were significantly associated to cognitive func-
tion (Table 1). There was significant evidence for interaction
Table 1Effect of APOE genotype on cognitive tests and cardiovascular factors by age category.
Systolic blood pressure (mmHg/cm)
Diastolic blood pressure (mmHg/cm)
Fasting glucose (mmol/l)
Serum cholesterol (mmol/l)
Serum Triglycerides (mmol/l)
Serum HDL (mmol/l)
Cognition test scores
AVLT short-term memory
WAIS verbal fluency
WAIS block design
Cognition compound scores
Overall cognitive function
Except TMT and Stroop, higher absolute values indicate better cognitive performance. P1: P-value adjusted for age, sex, inbreeding, and family relationship for all analysis; additionally adjusted for education and DART score for analysis of cognition. P2: P-value additionally
adjusted for total cholesterol, triglycerides, HDL, and IMT.
P values ≤0.05 are indicated in bold.
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F. Liu et al. / Neurobiology of Aging 31 (2010) 1831–1833
Fig. 1. Age-specific effect of the APOE E4 allele on AVLT learning scores.
between APOE*E4 and age. The interaction term of age
and APOE*E4 was significant for AVLT short-term memory
(Pinteraction=0.01), AVLT learning (Pinteraction=0.05), and
delayed recall (Pinteraction=0.09) and AVLT recognition
(Pinteraction=0.07), the evidence was borderline significant.
The APOE*E4 allele is significantly associated with
reduced memory performance in persons aged 50 years and
significant evidence for interaction between APOE*E4 and
age. The effect of APOE*E4 on memory become increas-
scores, although early effects can be seen by age 40 years for
factors may potentially be an intermediate feature explaining
part of the association between APOE and cognitive func-
tion. As expected, we observed a strong association between
HDL. Of the cardiovascular risk factors studied, IMT and
systolic blood pressure were strongly associated to cogni-
tive function. However, adjusting for these factors had little
influence on the association of APOE*E4 to memory, sug-
gesting that the effect of APOE*E4 on memory performance
is independent of its effect on cardiovascular factors.
The previous meta-analysis showed that APOE*E4 was
significantly related to reduced global cognitive functioning,
is age-specific and most pronounced in the memory domain
recent prospective, population-based study in 5804 subjects
aged 70–80 years (Packard et al., 2007).
Some of the significant P-values could be explained by
false positive findings due to the large number of test that
were conducted. The traits tested here are highly correlated,
making it difficult to adjust P-values by a Bonferroni correc-
tion. However, multiple tests from single domains, such as
memory domain showed consistent and significant associa-
tion making it less likely to explain these findings by type 1
Our study suggests that APOE*E4 has an early effect on
cognitive function, most pronounced on the memory domain
pendent of its effect on vascular risk factors.
Conflict of interest
No authors have any conflict of interest to report that is
relative to this manuscript.
This work was supported by the joint grant from the
Netherlands Organization for Scientific Research (NWO,
91203014) and the Russian Foundation for Basic Research
(NWO-RFBR, 047.017.043), the Center of Medical Systems
Biology (CMSB), Hersenstichting Nederland, Internationale
Stichting Alzheimer Onderzoek (ISAO), Alzheimer Asso-
ciation project number 04516, Hersenstichting Nederland
project number 12F04(2).76, and the Interuniversity Attrac-
tion Poles (IUAP) program.
Appendix A. Supplementary data
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