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 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 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 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 CASES - MMSE < 24 - slow development of cognitive impairment - other forms of dementia excluded (CT exam.) CONTROLS - MMSE > 28 - same gender and age (± 5 years)

EPIDEMIOLOGICAL DATA 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 cases controls OR 95% CI p-value % CVD 52 % 43 %   1,44 0,94-2,19 0,089 Diabetes 29 % 38 %  0,67 0,44-1,02 0,062 Hypertension 69 %   79 %   0,57 0,36-0,92 0,022 Stroke 15 % 22 %   0,63 0,38-1,04 0,069 Head Injury 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.

GENETICS 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) ApoE4 allele significantly increase the risk of AD. (OR 2,52; 95% CI 1,832-3,482) 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 % patients (n=373) 5,23 70,64 24,13 controls (n=286) 10,49 78,32 11,19 OR 0,47 0,66 2,52 (95% CI) X (1,832-3,482)

Frequency of apolipoprotein E genotypes (%) E2/E2 E2/E3 E3/E3 E2/E4 E3/E4 E4/E4 patients (n=373) 0,27 6,97 47,45 2,95 39,41 controls (n=286) 0,70 17,48 59,80 2,09 19,58 0,35 OR X 1,41 2,67 8,66 (95% CI) 0,51 – 3,88 1,86 – 3,82 1,11 – 67,48 p-value 0,62 ˂0,0000 0,01

Genotypes ACE 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 (%) patients (n=384) 47,14 52,86 controls (n=287) 45,12 54,88 OR 1,08 0,92 (95% Cl) 0,87 – 1,34 0,74 – 1,14 p-value 0,472

Frequency of genotypes (%) II ID DD patients (n=384) 22,39 49,48 28,13 controls (n=287) 16,72 56,79 26,49 OR 1,43 0,75 1,09 (95% CI) 0,97-2,12 0,54-1,01 0,77-1,53

Conclusions – vascular risk factors In patients with AD were CVD more often in their history compare to controls but the difference was not significant. 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.

Conclusions – genetic risk factors 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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