engleski

Genetic analysis of catechol-O-methyl transferase in Alzheimer's disease

Alzheimer's disease (AD) is a growing public health problem, the major risk for dementia, frequently associated with psychotic symptoms. The causes of AD are still unknown, and it is assumed that various etiologies lead to the characteristic pathological changes. Around 5-10% of AD is influenced by genetic factors. The aim of the study was to determine the genetic variations in catechol-O-methyltransferase (COMT), the major dopamine (DA) degrading enzyme, in patients with AD. The most common polymorphism of COMT is a single base change which constitutes of guanine to adenine substitution at the exson 4 of the COMT gene. This is a functional polymorphism responsible for substantial variability in COMT enzymatic activity. At position 158, a valine is replaced by methionine. The valine allele is associated with high COMT activity, and up regulation of striatal DA activity, carrying an increased risk for schizophrenia and a susceptibility to psychosis in AD, whereas the methionine allele is associated with low COMT activity, and a higher propensity for violence and suicide. Methods: The diagnosis of the probable AD fulfilling NINCDS-ADRDA criteria was established according to the ICD- 10 and DSM-IV-TR criteria. Mini Mental Status Examination was used to assess the cognitive impairment. The study included 62 AD patients: 30 with late onset (AD started after 65 years of age) and 32 with early onset (AD started before 65 years of age), and 90 drug free healthy subjects. Genotyping methods: DNA isolated from blood by a standard salting out procedure was genotyped for the COMT G/A polymorphism with ABI Prism 7000 Sequencing Detection System apparatus (ABI, Foster City, USA) using Taqman-based allele- specific polymerase chain reaction assay (TaqMan Drug Metabolism assay), according to the procedure described by the Applied Biosystems, and using the primers and probes from Applied Biosystems (ABI, Foster City, USA). The homozygous GG (valine) genotype was found in 28%, homozygous AA (methionine) genotype in 20%, while heterozygous GA genotype was determined in 51% subjects, with no significant deviation from the Hardy - Weinberg distribution (p>0.50). The distribution of GG, AA and GA genotypes was 27, 27 and 47% for patients with late onset of AD ; 25, 22 and 53% for patients with early onset of AD ; and 30, 18 and 52% for control subjects, respectively. The frequency of the COMT genotype (2 =0.012 ; df=1 ; p=0.913) was similarly distributed among patients with early and late onset of AD, or between patients with AD and control subjects ( 2 =1.004 ; df=1 ; p=0.605). Conclusion: These preliminary data do not support the hypothesis that valine variant encoded by the G allele is associated with the occurrence of AD. COMT polymorphism modulates cognitive functions and high activity carriers, due to the different regulation between striatal and frontal DA activity, are prone to develop psychotic symptoms. Therefore, our further study will correlate COMT polymorphism with psychotic symptoms (delusions, hallucinations and nighttime disturbances) in AD.

Alzheimer's Disease; catechol-O-methyltransferase; polymorphism; cognitive impairment

Časopis je indeksiran u: Neuroscience Citation Index, EMBASE (Excerpta Medica).