Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index.

Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life-style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age.

Association between 5q23.2-located polymorphism of CTXN3 gene (Cortexin 3) and schizophrenia in European-Caucasian males; implications for the aetiology of schizophrenia.

BACKGROUND: The objective of the study was to examine several polymorphisms in DISC1 and CTNX3 genes as possible risk factors in schizophrenia. DISC1 (disrupted-in-schizophrenia 1) has been studied extensively in relation to mental disease while CTXN3, has only recently emerged as a potential "candidate" gene in schizophrenia. CTXN3 resides in a genomic region (5q21-34) known to be associated with schizophrenia and encodes a protein cortexin 3 which is highly enriched in brain. METHODS: We used ethnically homogeneous samples of 175 male patients and 184 male control subjects. All patients were interviewed by two similarly qualified psychiatrists. Controls were interviewed by one of the authors (O.S.). Genotyping was performed, following amplification by polymerase chain reaction (PCR), using fragment analysis in a standard commercial setting (Applied Biosystems, USA). RESULTS: We have found a statistically significant association between rs6595788 polymorphism of CTXN3 gene and the risk of schizophrenia; the presence of AG genotype increased the risk 1.5-fold. Polymorphisms in DISC1 gene showed only marginally statistically significant association with schizophrenia (rs17817356) or no association whatsoever (rs821597 and rs980989) while two polymorphisms (rs9661837 and rs3737597) were found to be only slightly polymorphic in the samples. CONCLUSION: Evidence available in the literature suggests that altered expression of cortexin 3, either alone, or in parallel with changes in DISC1, could subtly perturb GABAergic neurotransmission and/or metabolism of amyloid precursor protein (APP) in developing brain, thus potentially exposing the affected individual to an increased risk of schizophrenia later in life.

Effect of Physical Activity in Treatment of Paediatric Obesity.

The aim of the study was to compare the differences in anthropometric parameters, maximal oxygen uptake (VO2max) and physical activity (PA) between groups of 146 obese boys and 128 obese girls. We tried to describe the relationships between changes in PA and changes in VO2max, body fat, weight, waist circumference and hip circumference. We found statistically significant changes in VO2max and waist circumference only in the group of boys and significant changes in VO2max in the group of girls.

Perspectives in genetic prediction of Alzheimer's disease.

Alzheimer disease (AD) represents a group of multifactorial disorders characterized by a progressive decline of mental faculties eventually leading to dementia and death. Aging of human populations is behind the rapid worldwide increase in the prevalence of AD in recent decades. AD prevention critically depends on reliable AD-predictive genetic testing but its further development is delicately poised at present. New DNA-analyzing technologies such as the Next Generation Sequencing (NGS) have allowed rapid and comprehensive analysis of the genome and might have aided the research into the genetics of AD. However, discoveries of epigenetic mechanisms and non-coding forms of DNA and RNA - while helping to explain complexities of AD etiologies - have imposed additional challenges onto the AD diagnostics based on DNA analyses. Environmental factors can, via epigenetic mechanisms, modify both coding and non-coding DNA and this has to be respected in DNA testing, including NGS. Risk calculations based on the known odds and risk ratios for selected DNA polymorphisms are viable options at present, while the applications of neural network methodology seems the most promising way forward in the development of predictive AD tests in future.

Diabetes, hypertension and stroke - does Alzheimer protect you?

OBJECTIVE: The aim of our current research project is to further evaluate the role of risk factors in the pathogenesis of Alzheimer's disease; these include genetic variations, environmental factors and lifestyle issues. METHODS: We have been conducting an association study on 373 patients with Alzheimer's disease and 286 unrelated control individuals. The occurrence and the age of onset of diabetes and cardiovascular diseases were evaluated in both groups. Apolipoprotein E genotype was analyzed in all subjects by PCR method. RESULTS: We report that, in Czech population carrying ApoE4 allele increases risk of Alzheimer's disease 2.1-fold and genotype E4E4 increases the risk 8.4-fold. We have also identified a significant association between ApoE4 allele, Alzheimer's disease and hypertension. Hypertensive subjects with the ApoE4 allele have 1.5-fold greater risk of Alzheimer's disease. Thus, hypertension together with ApoE4 allele translates into 1.5-fold higher risk of AD. The most intriguing original finding in the present study is that Alzheimer's disease patients have significantly later onset of diabetes, hypertension and stroke in comparison with control subjects. This effect was not influenced by ApoE genotype. The diabetes appeared in AD patients on average more than 10 years later than in the control subjects (p<0.0001), hypertension was diagnosed 14 years later in AD patients (p<0.00001) and stroke occurred on average 6 years later (p<0.005), compared to the control group. CONCLUSIONS: Overall, in addition to the above novel findings, our study expands the data base on risk factors that could be used in near future when testing for the genetic risk of Alzheimer's disease.

Molecular mechanisms of neuropathological changes in Alzheimer's disease: a review.

More than 100 years after description of Alzheimer's disease (AD), two major pathological processes observed already by Alois Alzheimer, remain as the main explanation of the pathogenesis of Alzheimer's disease. Important molecular interactions leading to AD neuropathology were described in amyloid cascade and in tau protein function. No clinical trials with novel therapies based on amyloid cascade and tau protein hypotheses have been successful. The main aim of recent research is focused on the question what is primary mechanism leading to the molecular development of AD pathology. Promising explanation of triggering mechanism can be seen in vascular pathology that have direct influence on the development of pathological processes typical for Alzheimer disease. Novel insight into a number of cellular signaling mechanisms, as well as mitochondrial function in Alzheimer disease could also bring explanations of initial processes leading to the development of this pathology.

Interactive effect of MTHFR and ADRA2A gene polymorphisms on pathogenesis of schizophrenia.

OBJECTIVES: Increasing evidences support the importance of epigenetic control in schizophrenia pathogenesis. One of the enzymes involved in DNA methylation process through homocysteine metabolism is methylenetetrahydrofolate reductase (MTHFR). The most extensively studied variant in the MTHFR gene is the C677T polymorphism, resulting in reduced enzyme activity and elevated homocysteine level. METHODS: In sample of 192 schizophrenics and 213 healthy controls an increasing risk of schizophrenia associated with MTHFR 677 CT+TT genotype was found (OR=1.6, p=0.021). Association was also evaluated by considering the C677T polymorphism as an interaction with COMT Val158Met and ADRA2A C-1291G polymorphisms previously associated with schizophrenia risk using a logistic regression analysis. RESULTS: Previous studies of MTHFR*COMT (C677T*Val158Met) interaction in relation to schizophrenia resulted in inconsistent results. In our sample this interaction did not significantly differ between schizophrenics and control subjects. On the other hand analysis of MTHFR*ADRA2A (C677T*C-1291G) interaction revealed significant association between ADRA2A CC+CG genotype in the MTHFR TC+TT carriers (p=0.008). CONCLUSIONS: Our results support role of noradrenergic functions as well as previously proposed role of epigenetic control in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to prove our results.

Epidemiological of and risk factors for Alzheimer's disease: a review.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is a degenerative, incurable and terminal disease. The increasing prevalence of AD is, among other reasons, due to population aging, which is, to a certain extent, seen worldwide. Continuous advances in health care keep increasing life expectancy. Official statistics are likely to significantly underestimate the actual prevalence of AD. Alzheimer's disease represents an important public health problem. Its aetiology is still unknown and for this reason, it is necessary to study all potential risk factors which may contribute to the development of this disease. METHODS: We searched original and review articles addressing Alzheimer's disease using key words Alzheimer's disease, epidemiology, risk factors and prevention. We found and used one hundred and four references. CONCLUSIONS: Based on epidemiological studies, genetic studies, neuroimaging methods and neuropathology research, three basic etiological hypotheses of the development of AD have been formulated: genetic, vascular and psychosocial. At present, the level of evidence is insufficient for the etiological role of other factors, such as nutrition, occupational exposure to various substances and inflammation. From the point of view of early diagnosis and application of primary or secondary prevention principles, genetic factors are the most important.