Elzbieta Luczywek

Homocysteine, apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment.

Background: Alzheimer’s disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. Objective: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B12 and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. Methods: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B12 in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. Results: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B12 levels and MTHFR status. Conclusions: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.

Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease

As Alzheimers disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.

Behavioural Pathology in Alzheimer’s Disease with Special Reference to Apolipoprotein E Genotype

The aim of this study was to define the co-occurrence of behavioural symptoms and Alzheimer’s disease (AD) in relation to apolipoprotein E (APOE) genotype. Probable AD patients from the Alzheimer’s Day Clinic (n = 139) were assessed with the ‘Behavioural Pathology in Alzheimer’s Disease’ rating scale, and their APOE genotype was determined. This study demonstrated no relationship between presence of the APOE Ε4 allele and any of the behavioural symptoms assessed, including delusions, hallucinations, depression, activity disturbances, aggressiveness and anxiety. Activity disturbances, delusions, hallucinations and aggressiveness paralleled the severity of AD, increasing in frequency with the severity of the dementia. The prevalence of delusions, hallucinations, aggressiveness and depression were found to be associated with lower levels of education.

CYP46 : A risk factor for Alzheimer's disease or a coincidence?

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46). Although serum and cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol are altered during the progress of Alzheimers disease, studies carried out to date in different populations on the association of CYP46 gene polymorphisms and risk of AD have been inconclusive. In this report, we analyzed CYP46 polymorphisms in 215 Polish AD cases and 173 healthy individuals. A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced. We discovered a new single nucleotide substitution in CYP46 intron 2, but found no difference in particular genotype or allele frequencies between AD patients and controls. However, the GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. However, considering the extreme divergence of results obtained by different authors, a clear connection between the CYP46 gene and AD is questionable.

P1-189: Conversion to dementia over a five-year period among patients with mild cognitive impairment in a Polish follow-up study

90% power. A neuroimaging profile indicative of pre-clinical AD was determined by a linear classifier trained on discriminating patients diagnosed with AD from normal controls subjects. Results: A trial using the recruitment criteria of the ADNI study would expect a mean placebo arm rate of decline of 0.6 MMSE points/year and require a sample size of 1000 subjects/arm to detect a 50% reduction in mean rate of decline. A trial restricting to subjects with an ApoE E4 allele would expect a mean rate of decline 1.1 points/year and require 395 subjects/ arm to detect a 50% reduction in mean decline. A trial restricting to subjects with a neuroimaging profile consistent with pre-clinical AD would expect a mean rate of decline 1.4 points/year and require 261 subjects/arm. Conclusions: Enrichment strategies can improve the efficiency of secondary prevention trials. Statistical considerations of power and sample size are relevant to discussions of the relative merit of different enhancement strategies.

P2-196: Whether depressive symptoms/syndromes are predictors of progression in mild cognitive impairment?

(MCI) have been proposed, the predictive validity of them has not been examined. Objective(s): We aimed to examine the validity from a longitudinal community-based study in Japan. Methods: After obtaining informed consent, a community sample of 1490 dementia-free individuals aged 65 and older was followed using neurolopsychological tests covering 5 domains of cognition (memory, attention, language, visuo-spatial, and reasoning) for 3 years. According to the method of Busse et al.(cut-off point of severity level:1.0, 1.5, 2.0 SD, presence or absence of subjective cognitive decline), we defined 18 types of modified MCI definition originating from three types of MCI (MCI-amnestic, MCI-multiple domains slightly impaired, MCI-single non-memory domain) on the basis of the examination results at the baseline. We standardized the results of the tests taking age, sex, and years of education into consideration. Three years later, 1023 of the original dementia-free participants underwent the second examination using the results of the same tests as the baseline, and we made a diagnosis of normal, MCI, and dementia for each participant. Results: The incidence of dementia during the observation period was 3.8% (1.3%/year). The convert rates from MCI to dementia showed a wide range difference depending on the subset of MCI employed. All six types of MCI-amnestic showed higher diagnostic specificity (more than 96%) but lower sensitivity (10% and less) in general. The use of modified criteria of MCI-multiple domains slightly impaired (original criteria except for the report of subjective cognitive decline and 1.0 SD cut-off level) showed relatively higher sensitivity (31%) but lower specificity (82%) and positive predictive power (7.4%). Conclusions: We should know the difference in sensitivity and specificity according to the subset of MCI. The convert rate from MCI to dementia appears to be different between community-based and clinic-based studies.