ORIGINAL ARTICLE

Lack of association between apolipoprotein E genotypes and

cognitive performance in the non-demented elderly
Juliana Lima QUINTAS,
1,2
Vincius Carolino SOUZA,
3
Adriane Dallanora HENRIQUES,
4
Wilcelly MACHADO-SILVA,
4
Juliana Oliveira TOLEDO,
3
Cludio CRDOVA,
5
Clayton Franco MORAES,
2,6
Einstein Francisco CAMARGOS
1,2
and Otvio Toledo NBREGA
2,3
1
Geriatric Medical Centre, Hospital of the
University of Brasilia,
2
Graduation Program in
Medical Sciences,
3
Graduation Program in Health
Sciences,
4
Pharmacy School, University of Brasilia
and
5
Graduation Program in Physical Education,
6
Geriatric Service Hospital, Catholic University of
Brasilia, Brasilia, Brazil
Correspondence: Dr Otvio T. Nbrega PhD, Campus
Universitrio Darcy Ribeiro, Asa Norte, Braslia
DF 70910-900, Brazil. Email: nobrega@pq.cnpq.br;
otavionobrega@unb.br
Received 17 May 2013; revision received 28 July 2013;
accepted 5 August 2013.
Abstract
Aim: The 4 alelle of the apolipoprotein E gene is known to be a key genetic
risk factor for Alzheimers disease and possibly for other neurological disor-
ders. Some evidence in the literature indicates that the 4 allele interferes
with human cognition independently of chronological age and diagnosis of
Alzheimers disease. The present study investigated the correlation of allelic
variants of apolipoprotein E with the cognitive performance of elderly indi-
viduals without apparent cognitive impairment.
Methods: This was a cross-sectional analysis that included 213 non-
demented elderly individuals (age 60 years) from the Brazilian Federal
District. The analysis assessed the subjects for cognitive domains including
short- and long-term episodic memory, processing speed, and attention
and executive functions. Sociodemographic and other clinical characteris-
tics were gathered and analyzed as covariates.
Results: Being sufciently powered, the present study did not identify
differential performance across apolipoprotein E genotypes. There was no
inuence of age, gender, marital status, schooling, depressive symptoms or
use of central nervous system depressants when the analyses were con-
trolled for such factors.
Conclusions: Our ndings suggest that the 4 allele does not contribute to
detectable cognitive decline within the context of non-dementia.
Key words: age-associated memory problems,
apolipoprotein, cognitive functioning, genetics,
neuropsychology.
INTRODUCTION
Population ageing results in an increased prevalence
of neurodegenerative diseases, especially dementia.
Among the different forms of dementia, Alzheimers
disease (AD) is the most common, and its prevalence
has increased in recent decades.
1
AD causes a level
of cognitive and behavioural impairment that inter-
feres with everyday life activities and the quality of life.
It is characterized by memory impairment associated
with decit in at least one other cognitive function,
such as executive functions, language, or attention,
with the exclusion of other causes of dementia.
2
The markers and other features that allow for the
early diagnosis of AD, especially genetic markers, are
the subject of investigation.
3
The 4 allele of the
apolipoprotein E (ApoE) gene is the main genetic risk
factor for AD,
4
and it is possibly involved in other
neurological disorders.
5
ApoE is the lipoprotein present in the greatest
amount in the central nervous system (CNS), and the
brain represents the second most important site for
its synthesis in the entire human body. The allelic
variants of ApoE in chromosome 19 exhibit three main
isoforms (2, 3 and 4) and six different genotypic
combinations: three homozygous (2/2, 3/3 and
4/4) and three heterozygous (2/3, 3/4 and 2/4).
Although there is evidence regarding the specic
role that ApoE plays in the formation of amyloid
plaque and neurobrillary tangles as well as the asso-
ciation of these histopathological formations with the
bs_bs_banner
doi:10.1111/psyg.12029 PSYCHOGERIATRICS 2014; 14: 1116
11 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society
aetiology of AD, the underlying mechanisms are still
poorly understood.
6
From the clinical perspective,
there are doubts about when and how a given geno-
typic variant manifests phenotypically in human cog-
nition. In this regard, some evidence indicates that
allele 4 interferes with human cognition indepen-
dently of chronological age by determining signs and
symptoms compatible with cognitive decline in a
context devoid of dementia.
7,8
Another line of research
shows that the presence of this allele is a risk factor
for AD and an accelerator of cognitive loss once the
diagnosis is set, thus accounting for an allele-specic
contribution to the appearance and progression of the
disease.
9
Studies conducted with non-demented elderly
seek to identify impairment in cognitive ability that
might be associated with the genotype. Therefore, the
aim of the present study was to investigate the asso-
ciation between the allelic variants of ApoE and the
cognitive performance of elderly individuals who lack
apparent cognitive impairment.
MATERIALS AND METHODS
Study design and patients
This was a cross-sectional analytical study including
non-demented elderly individuals (age 60 years) that
was conducted from August 2009 to December 2010.
The subjects were admitted to a health promotion
programme for prevention of age-related chronic dis-
eases at one of two general geriatric outpatient clinics
in the metropolitan area of the Brazilian Federal Dis-
trict. Both institutions employ staff skilled at diagnos-
ing and managing cognitive disorders. Diagnoses of
dementia were made according to the DSM-IV crite-
ria.
2
At admission, all patients were assessed with a
validated Brazilian Portuguese version of the Mini-
Mental State Examination (MMSE). Medical records
were used only as source of preliminary information.
Considering the heterogeneity of the Brazilian popu-
lation, cut-off scores for the MMSE were set at 18 and
26 points for individuals with 7 years and 8 years
of formal education, respectively.
10
Also, individuals
exhibiting signs or symptoms of psychiatric disor-
ders (e.g. schizophrenia, schizoaffective disorders,
delusional or mood disorders, delirium or intense
agitation), dementia (e.g. Alzheimers, Parkinsons,
vascular, frontotemporal or Lewy bodies) or important
brain diseases/injuries (e.g. ischemic stroke, subdural
haematoma, haemorrhage or trauma) were excluded.
In addition, a patient was deemed cognitively pre-
served at the 1-year follow-up if none of these disor-
ders were indicated and there was no decline in
MMSE below the thresholds. All clinical assessments
were executed by two experienced geriatricians.
Genetic analysis
The total genomic DNA of each participant was col-
lected using routine laboratory procedures. The geno-
types of ApoE common alleles (2, 3 and 4) were
established according to a modied version of the
method developed by Donohoe et al.
11,12
Procedures
Interviews
Individuals without psychiatric disorders, dementia or
other neurological disorders were invited to partici-
pate in structured interviews to identify their sociode-
mographic and clinical characteristics. Data were
collected on identity, gender, date of birth, level of
schooling, marital status and medications used,
among others. During the interviews, disorders that
could interfere with a participants overall state of
health (e.g. cancer, epilepsy, immobility, and stroke),
such as important sensory (visual and/or auditory)
impairment and untreated sleep disorders, were iden-
tied by the clinical team and considered as further
exclusion criteria. Users of medications that might
interfere with cognition were also excluded from
the study; for this purpose, a user was dened as
any individual using a constant dose of prescribed
CNS depressants (antipsychotics, tricyclic antide-
pressants, benzodiazepines, anticonvulsants, and/or
sleep inducers) for at least 4 weeks prior to the initial
interview. The present study was approved by the
Research Ethics Committee of the School of Medicine
of the University of Brasilia (#016/2009) (Brasilia,
Brazil). This study was approved by the institutional
ethics committee and conducted according to the
Helsinki Declaration. Participation was voluntary, and
written informed consent was obtained from each
participant.
Neuropsychological tests
After the initial interview, the Geriatric Depression
Scale and the MMSE were applied.
13,14
The cognitive
tests administered to participants encompassed
J. L. Quintas et al.
12 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society
several cognitive domains, including short- and long-
term episodic memory, processing speed, and
attention and executive functions. The cognitive tests
included the Paired Associate Learning Test, forms I
(PAL-I) and II (PAL-II) of the Wechsler Memory Scale,
15
Digit Span Forward and Backward of the Wechsler
Adult Intelligence Scale-III,
16
simple reaction time
tests (Visual Attention Variables Tests, reaction time,
rate of false alarms, percentage of hits) and Tower of
Hanoi.
17,18
In the Digit Span test, the sum of each
participants time for Digit Span Forward and Digit
Span Backward was also considered as an indepen-
dent variable. For the Tower of Hanoi, two disks were
used for training and three for testing;
19
these disks
were used to assess the total time in seconds to
perform the task, the number of errors and the
number of correct movements. All neuropsychological
tests were administered by the same examiner.
Data analyses
The average values of the quantitative variables col-
lected in the cognitive tests were compared among
the genotypic groups using ANOVA when the distribu-
tion of variables was normal and the variance of each
genotype was constant; otherwise, the KruskalWallis
non-parametric test was used. The
2
test was used
to analyze the qualitative variables. The sociodemo-
graphic variables (gender, age, schooling and marital
status), depressive symptoms and the use of CNS
depressants were considered covariables. For vari-
ables where the distribution of errors in ANOVA did not
exhibit a normal distribution and the variance was
constant, Napierian logarithmic transformation was
used. Tukeys adjustment was used to adjust multiple
comparisons.
A multiple linear regression model was used to
determine the inuence of the sociodemographic vari-
ables, depressive symptoms and use of depressants
on the cognitive tests. The model included 11 predic-
tor variables for cognitive tests: age, schooling,
gender, marital status, the presence or absence of
depressive symptoms, the use of benzodiazepines,
antipsychotics, antidepressants, tricyclic antidepres-
sants, anticonvulsants or other drugs (such as anti-
hypertensive, hypoglycaemic, hypolipidaemic drugs
and bisphosphonates, which do not interfere with
the CNS). For the sample comprising 213 indi-
viduals, with a 5% signicance level and an effect size
between 0.10 and 0.64, the test power exceeded
85%. The data were analyzed using the software SAS
9.2 for Windows (Cary, NC, USA).
RESULTS
From a pool of 398 eligible, cognitively preserved
cases, we scheduled telephone and/or clinical inter-
views from July 2011 to December 2011. From this
group of 398 subjects, 5 were excluded due to impor-
tant auditory and/or visual impairment and 13 due to
active disease that affected the participants overall
state of health (e.g. cancer, epilepsy or immobility).
Furthermore, 13 patients had died before we con-
tacted them, and 147 refused or were unable to par-
ticipate in the study. Data from one patient were lost.
With these exclusions, the following genotypic fre-
quencies were obtained from 219 subjects: 2/2 (n =
0; 0%), 2/3 (n = 15; 6.8%), 2/4 (n = 6; 2.7%), 3/3
(n = 159; 72.6%), 3/4 (n = 34; 15.5%), and 4/4 (n =
5; 2.3%). As there is epidemiological and experimen-
tal evidence that the ApoE allele 2 plays a role in
preservation of cognitive function,
20
individuals with
genotype 24 were excluded from the analysis
because of the putative opposite effects of these
alleles in cognition. Therefore, the nal sample for
comparison of genotypes comprised 213 individuals,
including 187 women (87.8%). The mean age of the
nal sample was 72.9 1 6.1 years, with 5.6 1 4.6 years
of schooling on average. Most of the patients were
married (n = 86; 40.4%) or widowed (n = 82; 38.5%).
The average values and percentages of sociodemo-
graphic variables found in the nal sample did not
differ signicantly among the three genotype groups
analyzed (Table 1).
For inferential analysis, the genotypes were
clustered to clarify the differences between carriers
of different alleles as follows: carriers of 2 (23),
homozygous 3 (33), and carriers of 4 (4/4 +
3/4). The average performance in the cognitive
tests did not indicate signicant differences in skills
related to episodic memory, processing speed, and
attention and executive capabilities among the three
investigated genotype groups (Table 2). Also, the
covariables of age, gender, marital status, level of
schooling, depressive symptoms, and the different
classes of CNS depressants in use did not have a
signicant inuence on the model when the analyses
were controlled for such factors.
ApoE and cognition in older adults
13 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society
DISCUSSION
The present study did not identify a correlation
between classic genotypes of ApoE and differential
performances in a battery of neuropsychological tests
(MMSE, PAL-I, PAL-II, Digit Span Forward, Digit Span
Backward, the sum of the Digit Span tests, Tower of
Hanoi, and simple reaction time) in elderly individuals
clinically identied as having preserved cognitive
functions. Investigating the performance of elderly
subjects on cognitive tests requires judicious proce-
dures that are able to establish their cognitive integrity
in order to exclude those with mild cognitive impair-
ment and preclinical stages of AD. In this regard, our
study represents a contribution to the scientic litera-
ture because it was performed with a sample enrolled
in a prospective research project where clinical
follow-up was performed on a regular basis, thus
ensuring the exclusion of diseases and other variables
that might interfere with cognition, such as subclinical
and early cases of AD. Despite the exclusion criteria
used, the methodological rigour in the application of
tests and the control of confounding variables, such
as schooling, age, comorbidities, and use of medica-
tions, the observed differences between carriers
and non-carriers of a given ApoE allelic form were
not signicant. The multiple linear regression model
Table 2 Comparison of cognitive variables across the three groups of ApoE genotypes
Tests
Groups (mean 1 SD) P-value
3/3
(n = 159)
4/4 + 3/4
(n = 39)
2/3
(n = 15)
3/3 vs
4/4 vs 3/4
3/3 vs
4/4 + 3/4
3/3 vs
2/3
4/4 +
3/4 vs 2/3
MMSE 25.9 2.7 25.5 3.1 24.5 2.7 0.273 0.999 0.247 0.331
PAL-I 11.6 4.1 11.3 3.6 11.1 3.0 0.866 0.948 0.917 0.855
PAL-II 4.6 1.7 4.5 1.4 4.5 1.2 0.991 0.999 0.993 0.991
DSF 6.0 1.8 5.5 1.4 5.3 1.6 0.146 0.253 0.367 0.966
DSB 3.7 1.8 3.4 1.6 3.1 1.6 0.736 0.981 0.716 0.834
DSTotal 9.7 3.1 8.9 2.6 8.5 2.7 0.284 0.526 0.401 0.873
HanoiT 104.9 68.5 95.8 65.6 118.9 53.1 0.200 0.405 0.520 0.198
HanoiM 13.7 6.1 13.1 5.6 16.4 5.1 0.097 0.598 0.169 0.079
HanoiE 1.5 1.2 1.2 1.0 1.7 1.3 0.082 0.067 0.998 0.372
RT 482.7 85.7 470.1 56.7 460.1 65.5 0.217 0.469 0.321 0.835
% hits 93.5 12.7 96.3 8.0 91.7 11.2 0.279 0.257 0.998 0.577
xpFA 0.0 0.0 0.0 0.0 0.0 0.1 0.167 0.991 0.154 0.163
P-values were calculated using ANCOVA adjusted for sociodemographic data, depressive symptoms and use of depressant drugs. Multiple comparisons were
adjusted using Tukeys test. Napierian logarithmic transformation was used. % hits, percentage of correct hits in TEVA; ApoE, apolipoprotein E; DSB, Digit Span
Test Backward; DSF, Digit Span Test Forward; DSTotal, sum of DSF and DSB; HanoiE, number of errors in Tower of Hanoi; HanoiM, number of correct movements
in Tower of Hanoi; HanoiT, total time to perform Tower of Hanoi; MMSE, Mini-Mental State Examination; PAL-I, Paired Associate Learning Test, form I; PAL-II,
Paired Associate Learning Test, form II; RT, reaction time in TEVA; TEVA, Visual Attention Variables Test; xpFA, rate of false alarms in TEVA.
Table 1 Comparison of continuous and categorical variables across the three groups of ApoE genotypes
Variable
Groups
P-value 2/3 (n = 15) 3/3 (n = 159) 4/4 + 3/4 (n = 39)
Age, years (mean 1 SD) 74.5 6.7 72.7 6.1 73.5 6.1 0.780
Schooling, years (mean 1 SD) 5.0 5.1 6.0 4.7 5.1 4.4 0.343
Women, n (%) 14 (93.3) 142 (89.3) 31 (79.5) 0.194
Marital status, n (%)
Married 7 (46.7) 62 (39.0) 17 (43.6) 0.858
Widowed 4 (26.7) 62 (39.0) 16 (41.0)
Presence of depressive symptoms, n (%) 4 (26.7) 40 (25.2) 13 (33.3) 0.896
Use of benzodiazepines, n (%) 2 (13.3) 12 (7.5) 5 (12.8) 0.482
Use of antipsychotics, n (%) 0 (0.0) 01 (0.6) 0 (0.0) 0.843
Use of antidepressants, n (%) 1 (6.7) 22 (13.8) 9 (23.1) 0.226
Use of tricyclic antidepressants, n (%) 1 (6.7) 7 (4.4) 1 (2.6) 0.779
Use of anticonvulsants, n (%) 0 (0.0) 6 (3.8) 1 (2.6) 0.707
Use of other drugs, n (%) 14 (93.3) 142 (89.3) 32 (82.0) 0.369
Percentages are expressed within genotype. P-values for categorical analyses were obtained using the
2
test and those for continuous data with ANOVA.
Signicance veried with the KruskalWallis test. ApoE, apolipoprotein E.
J. L. Quintas et al.
14 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society
indicated that the lack of signicant differences
could not be attributed to the limited power of the
test, which varied between 0.86 and 1.00 for all
investigated variables.
There is no consensus in the literature on the pos-
sible correlation between ApoE genotypes and cog-
nitive performance in non-demented individuals. From
the histopathological point of view, the current notions
on the role of ApoE in the human brain assert that
it favours the deposition of beta-amyloid plaques,
21
increases the phosphorylation of protein tau,
22
and
impairs neuronal repair among 4 carriers compared
to non-carriers.
23
However, these histopathological
changes do not necessarily imply established demen-
tia, and there is a discussion as to whether there is
a denite phenotype associated with allele 4,
24
or
rather a particular trigger event that underlies the
pathological processes with which it is related.
23
Despite the differences between both theoretical
points of view, they share a common feature: the
signicant contribution of the allele 4 once repair/
compensation mechanisms have become decient
and the impairment of human cognition has become
apparent. Some studies have investigated the contri-
bution of the 4 allele to the clinical progression of
mild cognitive disorders;
25
they found that conversion
to AD was more frequent among carriers compared to
non-carriers.
26,27
However, the 4 genotype does not
seem necessary for the onset of the mild cognitive
impairment itself.
28
Although some research groups
work on the assumption of an association between
ApoE genotypes and cognitive performance under
the antagonistic pleiotropy hypothesis (better perfor-
mance in youth, worse status in old age),
29
our
ndings corroborate results in which differences
in cognitive performance are attributed to different
stages of life rather than to the 4 allele.
9,30
The mere
presence of the allele does not determine subclinical
phenotypes within a non-demented context. Accord-
ingly, mild cognitive impairment might be understood
as a symptom of subclinical stages inherent to the
heterogeneity of a condition as complex as Alzheim-
ers dementia, to which the phenotypic expression of
the 4 allele contributes.
With regard to the sensitivity of the selected tests,
they are widely used to assess specic cognitive
functions (episodic memory, working memory,
mental speed, reaction time) and due compensation
mechanisms in the ageing process, thus differing
from wider-scoped batteries of tests that aim to
assess overall cognitive performance.
31
Moreover,
these instruments also considered the ability of
participants to understand and execute the tasks
regardless of their age and level of schooling.
Despite our attempt to exclude subclinical dementia
by following up with each subject for at least 1 year,
the neuropsychological protocol employed herein
does not rule out the possibility of unnoticed mild
cognitive disorders and future decline or conversion
to dementia, which may be considered a limitation of
this study. Another consideration with regard to the
present study is that the cross-sectional design used
is unable to make direct causal relationships evident.
Future studies must consider using longitudinal
designs to ensure a systematic cognitive assess-
ment of groups of non-demented elderly individuals
who are or are not carriers of 4.
CONCLUSIONS
To summarize, our study did not nd a relationship
between ApoE genotypes and cognitive performance
in non-demented elderly individuals. Our ndings indi-
cate that the 4 allele does not promote detectable
cognitive disorder within the context of non-dementia.
ACKNOWLEDGMENTS
This work was supported by Fundao de Apoio
Pesquisa do Distrito Federal (grant number
193.000.449-2008), Fundao de Empreendimentos
Cientcos e Tecnolgicos (grant number 5563/2009)
and Universidade de Braslia (UnBDoc 121696/2011).
A fellowship for productivity in research from
Conselho Nacional de Desenvolvimento Cientco
e Tecnolgico was granted to O.T. Nbrega. The
authors have no conict of interest to report.
REFERENCES
1 Ferri CP, Prince M, Brayne C et al. Global prevalence of demen-
tia: a Delphi consensus study. Lancet 2005; 366: 21122117.
2 APA. Diagnostic and Statistical Manual of Mental Disorders, 4th
edn. Washington, DC: American Psychiatric Association, 1994.
3 Bertram L, Lange C, Mullin K et al. Genome-wide association
analysis reveals putative Alzheimers disease susceptibility loci
in addition to APOE. Am J Hum Genet 2008; 83: 623632.
4 Bookheimer S, Burggren A. APOE-4 genotype and
neurophysiological vulnerability to Alzheimers and cognitive
aging. Annu Rev Clin Psychol 2009; 5: 343362.
5 Yip AG, McKee AC, Green RC et al. APOE, vascular pathology,
and the AD brain. Neurology 2005; 65: 259265.
ApoE and cognition in older adults
15 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society
6 Moraes CF, Lins TC, Carmargos EF, Naves JOS, Pereira RW,
Nbrega OT. Lessons from genome-wide association studies
ndings in Alzheimers disease. Psychogeriatrics 2012; 12:
6273.
7 Tuminello ER, Han SD. The apolipoprotein E antagonistic
pleiotropy hypothesis: review and recommendations. Int J
Alzheimers Dis 2011; doi: 10.4061/2011/726197.
8 Caselli RJ, Reiman EM, Locke DE et al. Cognitive domain
decline in healthy apolipoprotein E epsilon4 homozygotes
before the diagnosis of mild cognitive impairment. Arch Neurol
2007; 64: 13061311.
9 Bunce D, Anstey KJ, Burns R, Christensen H, Easteal S. Does
possession of apolipoprotein E varepsilon4 benet cognitive
function in healthy young adults? Neuropsychologia 2011; 49:
16931697.
10 Castro-Costa E, Fuzikawa C, Uchoa E, Firmo JO, Lima-Costa
MF. Norms for the Mini-Mental State Examination: adjustment
of the cut-off point in population-based studies (evidences from
the Bambui health aging study). Arq Neuropsiquiatr 2008; 66:
524528.
11 Donohoe GG, Salomaki A, Lehtimaki T, Pulkki K, Kairisto V.
Rapid identication of apolipoprotein E genotypes by multiplex
amplication refractory mutation system PCR and capillary gel
electrophoresis. Clin Chem 1999; 45: 143146.
12 Paula RS, Souza VC, Benedet AL et al. Dietary fat and
apolipoprotein genotypes modulate plasma lipoprotein levels
in Brazilian elderly women. Mol Cell Biochem 2010; 337: 307
315.
13 Yesavage JA, Brink TL, Rose TL et al. Development and valida-
tion of a geriatric depression screening scale: a preliminary
report. J Psychiatr Res 1982; 17: 3749.
14 Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A
practical method for grading the cognitive state of patients for
the clinician. J Psychiatr Res 1975; 12: 189198.
15 Wechsler D. WMS-III Wechsler Memory Scale, 3rd edn. San
Antonio, TX: Psychological Corporation, 1997; Manual.
16 Wechsler D. WAIS-III Wechsler Adult Intelligence Scale, 3rd edn.
San Antonio, TX: Psychological Corporation, 1997; Manual.
17 Crdova C, Bravin AA, Barros JF. TEVA: programa
computadorizado para registro e processamento da ateno
visual em investigaes com retardados mentais leves.
Lecturas Educacin Fsica Y Deportes 2005; 10: 5 (in Brazilian
Portuguese).
18 Sullivan JR, Riccio CA, Castillo CL. Concurrent validity of the
tower tasks as measures of executive function in adults: a
meta-analysis. Appl Neuropsychol 2009; 16: 6275.
19 Ahonniska J, Ahonen T, Aro T, Tolvanen A, Lyytinen H.
Repeated assessment of the Tower of Hanoi test: reliability and
age effects. Assessment 2000; 7: 297310.
20 Corder EH, Lannfelt L, Bogdanovic N, Fratiglioni L, Mori H. The
role of APOE polymorphisms in late-onset dementias. Cell Mol
Life Sci 1998; 54: 928934.
21 Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the
vast majority of AD risk and AD pathology. Neurobiol Aging
2004; 25: 641650.
22 Huang Y, Weisgraber KH, Mucke L, Mahley RW. Apolipoprotein
E: diversity of cellular origins, structural and biophysical prop-
erties, and effects in Alzheimers disease. J Mol Neurosci 2004;
23: 189204.
23 Laws SM, Hone E, Gandy S, Martins RN. Expanding the asso-
ciation between the APOE gene and the risk of Alzheimers
disease: possible roles for APOE promoter polymorphisms and
alterations in APOE transcription. J Neurochem 2003; 84: 1215
1236.
24 Greenwood PM, Parasuraman R. Normal genetic variation, cog-
nition, and aging. Behav Cogn Neurosci Rev 2003; 2: 278306.
25 Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA. Mild
cognitive impairment in different functional domains and inci-
dent Alzheimers disease. J Neurol Neurosurg Psychiatry 2005;
76: 14791484.
26 Kluger A, Ferris SH, Golomb J, Mittelman MS, Reisberg B.
Neuropsychological prediction of decline to dementia in
nondemented elderly. J Geriatr Psychiatry Neurol 1999; 12:
168179.
27 Vos SJ, van Rossum IA, Verhey F et al. Prediction of Alzheimer
disease in subjects with amnestic and nonamnestic MCI.
Neurology 2013; 80: 11241132.
28 Heun R, Guhne U, Luck T et al. Apolipoprotein E allele 4 is not
a sufcient or a necessary predictor of the development of Mild
Cognitive Impairment. Eur Psychiatry 2010; 25: 1518.
29 Alexander DM, Williams LM, Gatt JM et al. The contribution of
apolipoprotein E alleles on cognitive performance and dynamic
neural activity over six decades. Biol Psychol 2007; 75: 229
238.
30 Jorm AF, Mather KA, Butterworth P, Anstey KJ, Christensen H,
Easteal S. APOE genotype and cognitive functioning in a large
age-stratied population sample. Neuropsychology 2007; 21:
18.
31 Strauss E, Sherman EMS, Spreen O. A Compendium of
Neuropsychological Tests: Administration, Norms, and Com-
mentary, 3rd edn. Oxford and New York: Oxford University
Press, 2006.
J. L. Quintas et al.
16 2013 The Authors
Psychogeriatrics 2013 Japanese Psychogeriatric Society