Transcript genetic risk factors

EPIDEMIOLOGY AND
GENETICS OF ALZHEIMER´S
DISEASE
Jana Povova, Omar Sery, Hana Tomaskova, Petr Ambroz,
Anna Pohlidalova, Vladimir Janout
Department of Epidemiology and Public Health, Ostrava, Czech Republic
Department of Biochemistry, Brno, Czech Republic
INTRODUCTION
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It is generally accepted that Alzheimer´s
disease (AD) is the most frequent form of
dementia.
Etiology of AD is still unknown and there
are three hypotheses, what risk factors are
responsible for development of the disease:
- vascular risk factors
- genetic risk factors
- behavioral risk factors
EPIDEMIOLOGY
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From different reasons there are no exact data
about the incidence and prevalence of AD
- no compulsory notification
- difficult to distinguish between different
forms of dementia
- no exact diagnostic test
There are mostly only estimates of real
incidence or prevalence … in the Czech
Republic 120 000 cases of AD notified
STUDY
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Since 2010 we have been performing an
epidemiological study to assess the importance
of selected risk factors from vascular and
genetic fields.
The aim of the study is to recruit 800 cases of
AD and 800 controls.
In this paper we report some preliminary
results from analyses of 394 cases and 287
controls.
DIAGNOSTIC CRITERIA
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CASES
- MMSE < 24
- slow development of cognitive impairment
- other forms of dementia excluded (CT exam.)
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CONTROLS
- MMSE > 28
- same gender and age (± 5 years)
EPIDEMIOLOGICAL DATA
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Recruitment: 394 Cases
130 Controls
Gender:
79 % females 76 % females
Age (average) 79
73
96,7 % of cases with late onset (after 65 years)
Education: in group of cases 49 % elementary,72 %
lower than high school
in group of controls 36 % high school
Clinical course: in 85 % slow
SELECTED VASCULAR RISK
FACTORS
RISK
FACTOR
cases
%
%
OR
CVD
52 %
43 %
Diabetes
29 %
Hypertension
Stroke
Head Injury
controls
95% CI
p-value
1,44
0,94-2,19
0,089
38 %
0,67
0,44-1,02
0,062
69 %
79 %
0,57
0,36-0,92
0,022
15 %
22 %
0,63
0,38-1,04
0,069
4%
6%
0,69
0,29-1,64
0,403
GENETICS
We start with focusing on genes:
- Apolipoprotein E (ApoE)
- Angiotensin Converting Enzyme (ACE)
 Gene for ApoE is found on chromosome
19q13.2 and has 3 major alleles 2,3,4.
• It has 6 genotypes depending on combination of
these three alleles.
• The allele 4 is the only confirmed genetic factor
contributing to both early and late onset of AD.
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GENETICS
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ACE gene is located on the chromosome 17q23
and has 2 major alleles I and D.
It has 3 genotypes depending on combination of
these two alleles.
It was reported that the ID and II genotypes are
associated with the risk of AD (DD genotype is
considered as neuroprotective).
Apolipoprotein E (ApoE)
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ApoE4 allele significantly increase the
risk of AD. (OR 2,52; 95% CI 1,8323,482)
In both files the genotype E3/E3 was most
frequent (cases 47 % and controls 60 %)
The frequency of genotype E4/E4 was in
cases 3 %, in controls 0,3 % only.
Frequency of apolipoprotein alleles %
E2
E3
E4
patients
(n=373)
5,23
70,64
24,13
controls
(n=286)
10,49
78,32
11,19
OR
(95% CI)
0,47
X
0,66
X
2,52
(1,832-3,482)
Frequency of apolipoprotein E genotypes (%)
E2/E2 E2/E3
patients
(n=373)
controls
(n=286)
OR
E3/E3
E2/E4
E3/E4
E4/E4
0,27
6,97
47,45
2,95
39,41
2,95
0,70
X
17,48
X
59,80
X
2,09
19,58
0,35
1,41
2,67
8,66
X
X
X
0,51 – 3,88 1,86 – 3,82 1,11 – 67,48
(95% CI)
X
p-value
X
X
0,62
˂0,0000
0,01
Genotypes ACE
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Allele I increases risk of AD (OR 1,08;
95% CI 0,87 – 1,34) but so far difference
is not significant.
In both files the genotype ID was most
frequent – cases 49 % and controls 57 %.
Genotype II was in cases in 22 % and in
controls in 17 % (marginal significant
difference – OR 1,43 95% CI 0,97-2,12)
Frequency of I, D alleles (%)
I
D
patients (n=384)
47,14
52,86
controls (n=287)
OR
45,12
54,88
(95% Cl)
1,08
0,87 – 1,34
0,92
0,74 – 1,14
p-value
0,472
0,472
Frequency of genotypes (%)
patients
(n=384)
controls
(n=287)
OR
(95% CI)
II
ID
DD
22,39
49,48
28,13
16,72
56,79
26,49
1,43
0,97-2,12
0,75
0,54-1,01
1,09
0,77-1,53
Conclusions – vascular risk factors
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In patients with AD were CVD more often in their history
compare to controls but the difference was not significant.
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Diabetes, stroke and hypertension were inversely related to
AD what is contrary to some published results.
In case of hypertension the inversal difference was
statisticaly significant. The same finding was published by
some other researchers.
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Conclusions – genetic risk factors
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Relationship between ApoE4 allele and AD
was confirmed in presented paper with high
statistical significance, what make it possible
diagnostic marker for AD.
In ACE gene was only marginal reliance of
alelle I presence and higher risk of AD
development.
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