Ágnes Fehér

Association Between Bdnf Val66met Polymorphism and Alzheimer Disease, Dementia With Lewy Bodies, and Pick Disease

A functional polymorphism of the brain-derived neurotrophic factor (BDNF Val66Met) has been reported to affect memory-related hippocampal activity. Apolipoprotein E (ApoE) gene polymorphism is known to be associated with Alzheimer disease (AD), dementia with Lewy bodies (DLB), and Pick disease (PiD). We tested the hypothesis that BDNF Val and ApoE ϵ4 alleles confer susceptibility to AD, DLB, and PiD. The study included 160 AD, 34 DLB patients, 38 autopsy-confirmed PiD, and 164 age-matched healthy control (HC) probands. The frequency of the BDNF Val allele was significantly higher in AD, but there were no statistical differences in the allele distribution in PiD or in DLB as compared with HC. The Val/Met genotype occurred with statistically significantly higher frequency in PiD than in HC. The ApoE ϵ4 allele was significantly overrepresented in all dementias as compared with HC. Genotypes containing both ApoE ϵ4 and BDNF Val alleles occurred more frequently in all investigated dementias than in HC. We suggest that the presence of the BDNF Val allele in itself and in combination with the ApoE ϵ4 allele can be risk factors for AD, and the results indicate a synergistic effect of the 2 polymorphisms on DLB and PiD risk.

Association between a variant of the sigma-1 receptor gene and Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder with complex etiology and strong genetic predisposition. A number of investigations support the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathophysiology of AD. We aimed to investigate the association between SIGMAR1 polymorphisms and late-onset AD, therefore we genotyped rs1799729 (GC-241-240TT) and rs1800866 (Q2P) in 322 Hungarian late-onset AD patients and 250 ethnically matched, elderly control individuals. The investigated polymorphisms were in nearly complete linkage disequilibrium resulting in the GC-Q and TT-P predominant haplotypes that were subjected to the statistical analyses. Our data demonstrates an association between the SIGMAR1 TT-P variant and the risk for developing AD (p=0.019), and a potential modest interaction effect (p=0.058) of the co-presence of the TT-P haplotype with apolipoprotein E4 allele on the risk for AD. Based on this mild significance, we could not fully support the hypothesis that TT-P haplotype in interaction with APOE E4 allele confers risk for developing AD.

Association between the ABCG2 C421A polymorphism and Alzheimer's disease

ATP binding cassette subfamily G member 2 (ABCG2) is involved in amyloid-β transport and was found to be significantly up-regulated in Alzheimers disease (AD) brain. A functional polymorphism of the ABCG2 gene (C421A; rs2231142) was genotyped in a sample of 299 Hungarian late-onset AD patients and 259 elderly, non-demented controls to investigate for the first time its association with AD, either alone or in combination with apolipoprotein E (APOE) ɛ2/ɛ3/ɛ4 polymorphism. A significantly increased susceptibility to AD (OR=1.741, 95% CI: 1.075-2.819, p=0.024) associated with ABCG2 C/C genotype was found when compared with the variant allele containing genotypes (CA and AA) as the reference category. Logistic regression analysis revealed a significant interaction effect between the ABCG2 C/C genotype and APOE ɛ4 allele on AD risk (p=0.003). It seems that the potential modest risk effect of the ABCG2 C/C genotype on AD risk is more pronounced in combination with the APOE ɛ4 allele. Further independent replications of our findings are required.

Association between a Genetic Variant of the Alpha-7 Nicotinic Acetylcholine Receptor Subunit and Four Types of Dementia

We tested the hypothesis whether the partially duplicated variant of α7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (–2 bp) polymorphism and apolipoprotein E (ApoE) ε4 allele confer susceptibility to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the –2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE ε4 allele is a risk factor for dementias. The –2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.

Association Study of Interferon-γ, Cytosolic Phospholipase A2, and Cyclooxygenase-2 Gene Polymorphisms in Alzheimer Disease

OBJECTIVE The increased production of proinflammatory mediators such as cytokines and prostaglandins may interact at multiple levels with neurodegeneration in Alzheimer disease (AD). This study was undertaken to evaluate the possible role of interferon-γ (IFN-γ) T+874A, cytoplasmic phospholipase A₂ (cPLA2) BanI, and cyclooxygenase-2 (COX-2) G-765C polymorphisms in AD. METHODS The study included 237 probable patients with AD who met the diagnostic criteria of National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association, and 245 probands in the healthy comparison (HC) group. RESULTS No significant difference in mean age or in the distribution of genders between AD and HC groups was found. The COX-2 G/G genotype was significantly more frequent in the AD, when compared with the HC group. There was no significant correlation between IFN-γ or cPLA2 genotypes and AD. CONCLUSIONS Our findings indicate that the COX-2 G/G genotype is associated with AD and support the involvement of COX-2 in AD etiology.

Serum adipokine levels modified by donepezil treatment in Alzheimer's disease

Neurotransmitter enhancement therapy with acetylcholinesterase inhibitors (AChEIs) is a clinically proven approach for patients with Alzheimers disease (AD). Donepezil is one of the three currently approved AChEIs for treating AD symptoms delaying the decline in cognitive function. In addition to cholinergic hypofunction, there are several factors in AD pathogenesis. For example, adipocytokines released from adipose tissue are also thought to play a role in the progress of dementia. Adipokines, i.e., leptin and adiponectin, are involved in the modulation of certain cognitive functions in the brain. The goal of our study was to elucidate effects of donepezil therapy on the serum levels of certain adipokines, such as leptin and adiponectin in AD patients. Clinically diagnosed mild-to-moderate AD patients (n = 26) were involved in this open-labeled, single-center, prospective self-control study. ApoE polymorphism, serum adiponectin, leptin, LDL, HDL, triglyceride levels, and BMI were determined before and at 12 and 24 weeks intervals of donepezil treatment, respectively. Twenty-four weeks of donepezil treatment induced a linear decrease of serum leptin levels (p = 0.013) and a linear elevation of serum adiponectin levels (p = 0.007). BMI (p < 0.001) and abdominal circumference (p = 0.017) were significantly lower at 24 weeks as compared to control values. None of the other examined metabolic parameters were changed during the treatment period. This previously unrecognized serum adipokine regulating potential of donepezil may be relevant in its therapeutic, disease modifying effect in AD by transferring protective (by increasing serum adiponectin levels) and detrimental (by decreasing serum leptin levels) effects onto the neurodegenerative process at the same time.

No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population

Calcium homeostasis modulator 1 (CALHM1), a promising candidate gene for Alzheimers disease risk, has been recently identified. We tested the hypothesis that the T-allelic variant of the CALHM1 rs2986017 polymorphism confers susceptibility to Alzheimers disease in a Hungarian case–control sample that was also genotyped for apolipoprotein E. This study included 238 probable patients with Alzheimers disease who met the diagnostic criteria for National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association and 202 elderly healthy control participants. We failed to detect an association between the CALHM1 polymorphism and the risk for Alzheimers disease (P=0.153 for genotypes and P=0.090 for alleles), nor did we find an effect on age at onset. However, a potential weak correlation between the presence of the T allele (CT and TT genotypestogether) and Alzheimers disease was observed (P=0.056).

ABCB1 C3435T polymorphism influences the risk for Alzheimer's disease.

To evaluate the association of ATP-binding cassette subfamily B member 1 (ABCB1) genetic variants with the susceptibility to Alzheimer’s disease (AD), we genotyped the rs1128503 (C1236T), rs2032582 (G2677T/A), and rs1045642 (C3435T) polymorphisms in a case–control sample (234 AD patients, 225 controls). Single-marker analyses revealed a significant association solely for the rs1045642 polymorphism (C/C genotype carriers had increased risk for AD), which remains significant after correction for multiple testing. Haplotype analyses indicated three nominally significant associations which were lost after applying multiple test correction.

Genetic analysis of the RELN gene: Gender specific association with Alzheimer's disease

Association between genetic variants of the reelin (RELN) gene and the risk for developing Alzheimers disease (AD) was examined in a sample of 432 patients and 308 controls. Single marker and haplotype analyses revealed that the strongly linked rs528528 and rs607755 polymorphisms are associated with AD risk in a gender specific manner. Among men, but not in women the rs528528 T/T and rs607755 A/A genotypes were significantly associated with the susceptibility to AD.

Gender dependent effect of DHCR24 polymorphism on the risk for Alzheimer's disease

A remarkable candidate gene for late-onset Alzheimers disease (AD) is 24-dehydrocholesterol reductase (DHCR24) gene that encodes seladin-1 (selective AD indicator), an enzyme that is involved in the cholesterol biosynthetic pathway, exerts neuroprotective and anti-apoptotic effects, and found to be down regulated in AD vulnerable brain regions. The genetic association between DHCR24 rs600491 polymorphism and the risk for AD was investigated in 295 Hungarian late-onset AD patients and 204 ethnically matched, elderly, cognitively healthy control individuals. The DHCR24 rs600491 genotype distributions did not differ significantly between the AD and control groups. Stratification according to gender, however, revealed a statistically significant association between T/T genotype and AD risk in men, in contrast with the results in women. Our findings indicate a gender dependent effect of DHCR24 rs600491 polymorphism on the susceptibility to AD.