To cite this article: Neuroendocrinol Lett 2014;35(8):691–696
ORIGINALARTICLE
Neuroendocrinology Letters Volume 35 No. 8 2014
ISSN: 0172-780X; ISSN-L: 0172-780X; Electronic/Online ISSN: 2354-4716
Web of Knowledge / Web of Science: Neuroendocrinol Lett
Pub Med / Medline: Neuro Endocrinol Lett
Diabetes, hypertension and stroke –
does Alzheimer protect you?
Omar Šerý1,2, Lýdia Hlinecká1, Vladimir J. Balcar3, Vladimír Janout4, Jana Povová4
1 Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of
Science, Masaryk University, Brno, Czech Republic
2 Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic
3 Discipline Anatomy and Histology and Bosch Institute, School of Medical Sciences, Sydney Medical
School, The University of Sydney NSW, Australia
4 Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Czech
Republic
Correspondence to: Assoc Prof. RNDr. Omar Šerý, PhD.
Laboratory of Neurobiology and Molecular Psychiatry,
Department of Biochemistry, Faculty of Science, Masaryk University,
Kotlářská 2, 611 37 Brno, Czech Republic.
tel: +420 549 497 312; fax: +420 542 213 827; e-mail: omarsery@sci.muni.cz
Submitted: 2014-11-12 Accepted: 2014-12-12 Published online: 2015-01-18
Key words: ApoE; hypertension; diabetes; stroke; association; polymorphism
Neuroendocrinol Lett 2014;35(8):691–696 PMID: 25702297 NEL350814A03 ©2014 Neuroendocrinology Letters • www.nel.edu
Abstract OBJECTIVE: The aim of our current research project is to further evaluate the role
of risk factors in the pathogenesis of Alzheimer’s disease; these include genetic
variations, environmental factors and lifestyle issues.
METHODS: We have been conducting an association study on 373 patients with
Alzheimer’s disease and 286 unrelated control individuals. The occurrence and
the age of onset of diabetes and cardiovascular diseases were evaluated in both
groups. Apolipoprotein E genotype was analyzed in all subjects by PCR method.
RESULTS: We report that, in Czech population carrying ApoE4 allele increases
risk of Alzheimer’s disease 2.1-fold and genotype E4E4 increases the risk 8.4-fold.
We have also identified a significant association between ApoE4 allele, Alzheimer’s
disease and hypertension. Hypertensive subjects with the ApoE4 allele have 1.5fold
greater risk of Alzheimer’s disease. Thus, hypertension together with ApoE4
allele translates into 1.5-fold higher risk of AD. The most intriguing original
finding in the present study is that Alzheimer’s disease patients have significantly
later onset of diabetes, hypertension and stroke in comparison with control subjects.
This effect was not influenced by ApoE genotype. The diabetes appeared
in AD patients on average more than 10 years later than in the control subjects
(p<0.0001), hypertension was diagnosed 14 years later in AD patients (p<0.00001)
and stroke occurred on average 6 years later (p<0.005), compared to the control
group.
CONCLUSIONS: Overall, in addition to the above novel findings, our study
expands the data base on risk factors that could be used in near future when testing
for the genetic risk of Alzheimer’s disease.
692 Copyright © 2014 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Omar Šerý, Lýdia Hlinecká, Vladimir J. Balcar, Vladimír Janout, Jana Povová
Abbreviations:
AD - Alzheimer’s disease
ANOVA - analysis of variance
ApoE - apolipoprotein E
ApoE4 - E4 allele of apolipoprotein E
APP - amyloid precursor protein
bp - base pair
CSS - computer statistic software
CT - computerized tomography
DMSO - dimethyl sulfoxide
DNA - deoxyribonucleic acid
ICD-10 - 10th revision of the International Statistical
Classification of Diseases and Related Health Problems
MMSE - minimental state examination
Ods - odds ratios
OR - odds ratio
PCR - polymerase chain reaction
INTRODUCTION
As the average age and longevity of world population
increase, the incidence and prevalence of Alzheimer‘s
disease (AD) is on the rise. In the near future, this may
lead to significant deterioration in the quality of human
life at both individual and social level. Greater knowledge
of AD pathogenesis and related risk factors would
offer hope for better prevention of Alzheimer‘s disease
and/or mitigation of some of the associated adverse
effects leading to potentially very significant beneficial
outcomes (Šerý et al. 2014).
Risk factors for the pathogenesis of Alzheimer’s disease
(AD) are multiple and wide-ranging, including
cerebrovascular and cardiovascular diseases (particularly
hypertension), smoking, high or moderate alcohol
intake, obesity, hypercholesterolemia, diabetes mellitus,
education and socioeconomic status, and both physical
and mental activity (for review see Povova et al. 2013).
There are several specific examples of how the above
factors can alter the risk of AD. The presence of type II
diabetes has been reported as associated with an approximately
twofold increase in the risk of AD (Mayeux &
Stern 2012). The relationship of hypertension to AD has
been assessed from two perspectives. The first aspect
involved the study of the relationship between AD and
hypertension in middle age, the second aspect focused
on the hypertension in later life. The onset of hypertension
during the middle age appears to increase the risk
of AD pathogenesis in persons that do not have their
blood pressure adequately treated and controlled (Feldstein
2012). The relationship between the late age onset
hypertension and AD is more complex (Mayeux &
Stern 2012); abnormally low blood pressure is also associated
with dementia and it may be related to worsen-
ing of the brain hypoperfusion (Feldstein 2012). Recent
studies have reported a close link between sporadic AD
and ischemic brain episodes (Pluta et al. 2012). There
are several explanations of vascular pathology in AD
including iron-induced fibrin formation (Lipinski &
Pretorius 2013; Lipinski & Pretorius 2014).
The apolipoprotein E genotype with known links
to dynamics of cholesterol transport has been implicated
as a vascular risk factor in influencing AD (Šerý
et al. 2013). Cerebral hypoperfusion may initiate and/
or accelerate the neurodegeneration cascade causing
amyloid deposition, synaptic and neural dysfunction
and lead to cognitive impairment (Pluta et al. 2013).
Aβ deposition into the capillary wall is strongly associated
with the ApoE4 allele as a risk factor (Attems et al.
2010).
The primary aim of the present study has been to
investigate the effect of the ApoE genotype (rs 429358
and rs7412) on the risk of Alzheimer‘s disease with a
particular focus on a possible correlation between AD
and the occurrence of hypertension, stroke, type II diabetes
and selected lifestyle risk factors.
MATERIALS & METHODS
Subjects
We examined a total of 373 patients with Alzheimer’s
disease and 286 unrelated control individuals originating
from the Czech Republic. The group of patients
with AD (age 79.5±8.1) was diagnosed according to the
criteria of International Classification of Diseases 10th
Revision (ICD-10); additionally 211 patients underwent
CT scans to verify the diagnosis. Patients were
hospitalized with diagnosis of AD in Psychiatric hospitals
Kroměříž, Šternberk, Jihlava, Moravský Beroun and
Opava. Control subjects (age 70.8±9.6) were enrolled
in various other departments (eye clinics, traumatology
clinic) in hospitals Kromeříž, Olomouc and in the Faculty
Hospital of Masaryk University in Brno-Bohunice.
Some control subjects were life partners (spouses) of AD
subjects. In the control group the presence of dementia
was excluded using the minimental state examination
(MMSE) and interviews with psychiatrists. Informed
consent was obtained from all participants or their
legal representatives and formal approval for the study
was granted by the Ethics Committee of the Faculty of
Medicine, University of Ostrava.
The questionnaires for both groups – patients and
controls – contained questions about vascular risk factors
such as smoking, alcohol consumption, weight and
height, the age of onset of diabetes, stroke and hypertension
and its therapy, selected nutritional factors,
presence of other cardiovascular and cerebrovascular
diseases, and a history of head injury. Answers of AD
patients were based on the medical records collected by
physicians. The questions related to psychosocial factors
such as education and socioeconomic level, social network
and the extent of social engagement of each individual,
as well as those related to physical and mental
activities were also included in the questionnaire.
Genotyping
DNA from buccal swabs was isolated according to the
modified protocol of Prepito NA Body Fluid Kit on
693Neuroendocrinology Letters Vol. 35 No. 8 2014 • Article available online: http://node.nel.edu
Does Alzheimer protect you?
automated system Prepito (chemagen – Perkin Elmer,
USA). The ApoE gene sequence with rs 429358 and
rs7412 polymorphic sites was amplified using the polymerase
chain reaction (PCR). Each PCR mix contained
1 μl of extracted DNA (50ng/μl), DNA polymerase
KAPA2G Robust HotStart (Kapa Biosystems, Japan), 1%
7-deaza-dGTP (Roche Diagnostics, USA), 5% DMSO
and PCR water in final volume of 20μl. The labelled oligonucleotide
primers Apo1 FAM – 5´CGG ACA TGG
AGG ACG TG 3´ and Apo2 TAMRA – 5´CCC CGG
CCT GGT ACA CT 3´ were used. Special polymerase
KAPA2G Robust HotStart, DMSO and 7-Deaza-dGTP
were used for PCR mixture because of high content of
G+C bases in nucleotide sequence of ApoE gene. The
PCR conditions were: initial denaturation at 95°C for
10 min, followed by 35 cycles of denaturation 95°C for
1 min, annealing at 58°C (with 20% ramp) for 30 s and
elongation at 72°C for 60 s. A final extension at 72°C
for 7 min was included.
The PCR products were digested with Hha 1 restriction
enzyme to recognize rs 429358 and rs7412 polymorphisms.
The mixture was incubated at 37°C for
30min and 95°C for 5 min. Restricted DNA fragments
were denatured by formamide. Finally, fragments were
separated by capillary gel electrophoresis on an automated
Genetic Analyzer ABI 3130 (Applied Biosystems,
USA).
Statistics
The CSS Statistica software (StatSoft, USA) was used
for statistical evaluation of the results. The chi-square
test and Fisher’s exact test were used for the comparison
of genotype and allele frequencies in the studied
groups. Odds ratios (Ods) and 95% confidence intervals
(95% CI) as estimates of the relative risk for the
AD associated with different genotypes were calculated
with logistic regression. One-way analysis of variance
(ANOVA) was used to determine whether there are
any significant differences between the means of two or
more independent groups.
RESULTS
The comparison between AD patients and control
subjects in scores of the minimental state examination
(MMSE) is shown in Figure 1 (p<0.00001).
ApoE genotype was successfully analyzed in all 659
subjects and separate association analyses between
ApoE genotype and Alzheimer’s disease, diabetes,
hypertension and stroke are displayed in Table 1.
The frequency of ApoE4 allele is significantly higher
in AD patients in comparison with control subjects
(p=0.00001). The presence of ApoE4 allele in the
genotype significantly (p<1 × 10–9, two tailed Fisher
Exact Probability Test) increases the risk of AD 2.1fold
(Odds Ratio = 2.9324; 95% CI of OR = 2.0745 till
4.1449, Risk Ratio = 2.0569; 95% CI of OR = 1.6101
till 2.6276). The ApoE gene genotype E4E4 significantly
(p<0.02) increases risk of AD in carriers 8.4-fold (Odds
Ratio = 8.6602; 95% CI of OR = 1.1115 till 67.4758, Risk
Ratio = 8.4343; 95% CI of OR = 1.0952 till 64.9526).
The ApoE gene genotype E3E4 increases risk of AD
Tab. 1. The relationship between cases and controls for Alzheimer’s disease, diabetes, hypertension and stroke in the ApoE genotype and
alleles.
ApoE genotype Frequency of E2, E3, E4 alleles (%)
F-test χ2
E2/E2 E2/E3 E2/E4 E3/E3 E3/E4 E4/E4 E2 E3 E4
AD case 1 26 11 177 147 11 5.2 70.6 24.1 <0.00001 0.26
control 2 50 6 171 56 1 10.4 78.3 11.2
diabetes case 0 15 7 90 58 3 6.3 73.1 20.6 0.76 0.068
control 3 41 10 217 132 9 6.9 73.6 19.4
hypertension case 2 54 13 239 141 6 7.8 73.9 18.2 0.68 0.066
control 1 22 4 97 61 6 7.3 72.5 20.2
stroke case 0 9 4 52 25 4 6.9 73.4 19.7 0.43 0.099
control 3 66 13 284 177 8 7.7 73.6 18.7
Controls
12
14
16
18
20
22
24
26
28
30
32
MMSEscore
Alzheimer's patients
Fig. 1. The comparison of MMSE score between Alzheimer‘s
patients and controls. F=969.06; p<0.00001.
694 Copyright © 2014 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Omar Šerý, Lýdia Hlinecká, Vladimir J. Balcar, Vladimír Janout, Jana Povová
two-fold (Odds Ratio = 2.6715; 95% CI of OR = 1.8668
till 3.8229, Risk Ratio = 2.0127; 95% CI of OR = 1.5419
till 2.6273, p<1 × 10–7). In contrast, the risk of AD is
significantly decreased (0.4-fold; p<0.0001) in carriers
of E2E3 genotype (Odds Ratio = 0.3537; 95% CI of OR
= 0.2141 till 0.5842, Risk Ratio = 0.3987; 95% CI of OR
= 0.2547 till 0.6242).
ApoE genotype has not been found to be associated
with diabetes, hypertension and stroke in mixed groups
of AD subjects and controls (Table 1). Neither have we
found any significant relationship when we grouped
the subjects into AD patients and controls and studied
allelic frequency differences between ApoE and diabetes,
hypertension and stroke separately in each group
(Table 2). The last section of Table 2 represents the frequency
of ApoE genotype in diabetes, hypertensive and
stroke patients in the group of AD patients and the same
relationships in the group of AD controls. We found a
significant association between ApoE genotype and
hypertension, when we compared hypertensive patients
in AD group and AD controls (p<0.0001), see Table 2.
In the group of all hypertensive subjects the presence
of ApoE4 allele statistically significantly (p=0.000001)
increases risk (1.5-fold) of Alzheimer’s disease (Odds
Ratio = 2.7912; 95% CI of OR = 1.8459 till 4.2204, Risk
Ratio = 1.5038; 95% CI of OR = 1.2895 till 1.7536). The
presence of ApoE4 allele together with hypertension
increases the risk of AD 1.5-fold.
The risk of AD in relatives of AD patients with presence
of ApoE4 allele is 2.82× higher (Odds Ratio =
3.0658; 95% CI of OR = 1.3968 till 6.7291, Risk Ratio
= 2.8256; 95% CI of OR = 1.3568 till 5.8842). Tobacco
smoking had a marginal but statistically significant
(p=0.001) effect increasing the risk of AD in our group
of subjects 1.13-fold (Odds Ratio = 1.8935; 95% CI of
OR = 1.2881 till 2.7834, Risk Ratio = 1.1295; 95% CI of
OR = 1.0459 till 1.2198).
We found that the onset of diabetes, hypertension
and stroke in patients with AD took place later than
in the control group. This effect was not influenced by
ApoE genotype. The diabetes appeared in AD patients
on average more than 10 years later than in the control
subjects (p<0.0001), hypertension was diagnosed
14 years later in AD patients (p<0.00001) and stroke
occurred on average 6 years later (p<0.005), compared
to the control group (Figures 2–4).
Tab. 2. The comparison of occurence of diabetes, hypertension and stroke between ApoE genotypes in the group of Alzheimer’s patients
and controls.
    ApoE genotype
    E2/E2 E2/E3 E2/E4 E3/E3 E3/E4 E4/E4 χ2
Alzheimer’s disease group
diabetes yes 0 8 5 49 44 3 0.075
no 1 18 6 128 103 8
hypertension yes 1 17 8 123 102 6 0.098
no 0 9 3 53 44 6
stroke yes 0 4 2 31 18 3 0.091
no 1 21 9 145 128 8
Group of controls
diabetes yes 0 7 2 41 14 0 0.101
no 2 23 4 89 29 1
hypertension yes 1 37 5 116 39 1 0.074
no 1 13 1 44 17 0
stroke yes 0 5 2 21 7 1 0.183
no 2 45 4 139 49 0
Alzheimer’s disease patients (AD) vs. controls (cont.)
diabetes cont. 0 7 2 41 14 0 0.049
AD 0 8 5 49 44 3
hypertension cont. 1 37 5 116 39 1 p<0.0001
AD 1 17 8 123 102 6
stroke cont. 0 5 2 21 7 1 0.578
AD 0 4 2 31 18 3
695Neuroendocrinology Letters Vol. 35 No. 8 2014 • Article available online: http://node.nel.edu
Does Alzheimer protect you?
DISCUSSION
Many studies have reported diabetes, hypertension and
stroke as risk factors in the pathogenesis of Alzheimer’s
disease. We decided to analyze the relationship between
these cardiovascular diseases and apolipoprotein E
genotypes in a group of 659 AD patients and controls
of Czech origin. ApoE genotype frequencies in our
study (E2E2 0,005, E2E3 0.115, E2E4 0.026, E3E3 0.528,
E3E4 0.308, E4E4 0.018) were similar to the frequencies
recently reported for Czech population by Hubáček et
al. (2013) – E2E2 0.007, E2E3 0.117, E2E4 0.02, E3E3
0.66, E3E4 0.187, E4E4 0.009. Hubáček et al. (2013)
studied the association between ApoE genotype and
left-handedness on general Czech population and did
not specifically focus on any pathological condition
including AD. Somewhat higher count of genotypes
containing ApoE4 allele present in our data may be
caused by the particular design of our study – we had a
higher number of AD patients in our group of subjects.
The data in the present study are in accordance with
previously extensively described relationship between
ApoE genotype and Alzheimer’s disease (reviews: Šerý
et al. 2013; Armstrong 2013). We found that ApoE4
allele occurs at significantly higher frequency in AD
patients in comparison with control subjects (p=0.004).
In quantitative terms the results of our study translate
into ApoE4 allele presence in genotype increasing the
risk of AD 2.1-fold (p<1 × 10–9). Carrying of the genotype
E4E4 increases the risk of AD 8.4-fold (p<0.02).
AD patients in our study carrying ApoE4 allele were
found to have 2.82-times greater number of relatives
with AD in comparison with control subjects. Our data
are comparable to those obtained using other population
groups (for recent review see Raichlen & Alexander
2014).
Tobacco smoking also significantly (p=0.001)
increased the risk of AD (the effect was not very strong,
though; 1.13-fold difference) in our group of subjects;
this is in agreement with the findings of recent studies
(Povová et al. 2012).
Dembińska-Kieć et al. (1998) were the first to suggest
that the ApoE phenotypes and insulin output may
contribute to an early detection of individuals at high
risk of  hypertension  development. Their study suggested
that elevated levels of blood pressure in middle
age can increase the risk of late age-onset dementia in
men never treated with anti-hypertensive medication.
Launer et al. (2000) found the relationship between
elevated levels of blood pressure in middle age and an
increased risk of dementia at later age in men never
treated with anti-hypertensive medication. Yilmaz et al.
(2001) reported a trend for ApoE4 allele to be associated
with a higher prevalence of target organ damage in
patients with mild to moderate hypertension. Li et al.
(2003) reported similar findings in Chinese population.
In hypertensive patients with apolipoprotein E3E4 and
E4E4 genotypes, systolic blood pressure was signifi-
54
56
58
60
62
64
66
68
70
72
74
76
Ageofonsetofdiabetes
ControlsAlzheimer's patients
52
54
56
58
60
62
64
66
68
70
Ageofonsetofhypertension
ControlsAlzheimer's patients
58
60
62
64
66
68
70
72
74
76
78
Ageofonsetofstroke
ControlsAlzheimer's patients
Fig. 2. The comparison of age-onset of diabetes between
Alzheimer‘s patients and controls. F=16.590, p=0.0001.
Fig. 3. The comparison of age-onset of hypertension between
Alzheimer‘s patients and controls. F = 25.264, p<0.00001.
Fig. 4. The comparison of age-onset of stroke between Alzheimer‘s
patients and controls. F = 8.3891, p=0.00471.
cantly higher than in those with apolipoprotein E2E3
or E3E3 genotypes.
In our study the presence of ApoE4 allele combined
with hypertension increases the risk of AD 1.5-fold.
Our findings may be explained by those of Kesler et
al. (2010). Kesler et al. (2010) reported that in ApoE4
allele carriers, hypertension was associated with higher
696 Copyright © 2014 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Omar Šerý, Lýdia Hlinecká, Vladimir J. Balcar, Vladimír Janout, Jana Povová
tau and ptau-181 levels in cerebrospinal fluid. In their
study, the hypertension was not associated with Abeta42
levels, and ApoE genotype did not modify this relationship.
Kester et al. (2010) suggested that the hyperten-
sion  is directly related to Tau pathology in  ApoE4
homozygous carriers. ApoE4 allele seems to mediate
hyperphosphorylation of Tau protein (Rahman et al.
2005). Hypertension itself in ApoE4 carriers seems to
accelerate AD pathophysiology via higher Tau protein
levels.
What seems to be a very curious and unusual finding
in the present study is that AD patients have significantly
delayed onset of diabetes, hypertension and
stroke in comparison with the control subjects. This
effect appears to be unrelated to the ApoE genotype.
It is based on histories of patients collected from their
hospital and clinical records. We concede that the
records might contain occasional errors, but the difference
that we found is so large and the associated statistical
significance so high that we do not believe that the
result could have been produced merely by inaccuracies
in the patients’ records. Are cardiovascular diseases
really risk factors of AD? Yes, indeed; our study does
not cast serious doubt on that relationship per se. It does
appear, however, that patients with AD may be “protected”
against cardiovascular diseases and diabetes for
a period of time but, as soon as the cardiovascular disease
or diabetes appear, they are quickly followed by the
onset of AD symptoms. A possible explanation of one of
the present findings is offered by recent results of Wang
et al. (2014); insulin could inhibit Abeta production
through modulation of APP processing by increasing
APP cleavage at the alpha-secretase site and decreasing
the cleavage at the beta-secretase site. Disturbances in
the insulin levels associated with the onset of diabetes
could then accelerate the development of AD pathology
and bring forward the time when it first manifests itself
as dementia.
Stated in more general terms, persons at high risk
of AD may experience a degree of apparent protection
(mediated by as yet unidentified factors) from cardiovascular
disease and diabetes during their middle or
late-middle age but, when those conditions develop
they are rapidly followed by onset/deterioration in AD.
We have at present no mechanistic explanation of this
relationship at a molecular and cellular level but, based
on available patient data, it does not appear to have
been caused by any obvious trivial factors.
ACKNOWLEDGMENTS
This work has been supported by Internal grant agency
of the Ministry of Health of the Czech Republic (IGA
MZCR) No. NT/11152-6.
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