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Sexually Dimorphic Effect of the Val66Met Polymorphism of BDNF on Susceptibility to Alzheimer's Disease: New Data and Meta-Analysis

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 01/2009; 153B(1):235-42. DOI: 10.1002/ajmg.b.30986
Source: PubMed

ABSTRACT Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.

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Available from: Benedetta Nacmias, Mar 10, 2014
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    • "In humans, a cross-continent meta-analysis found that the Met66 polymorphism of the BDNF gene, shown to reduce the transport of BDNF, conferred an increased risk of AD in women but not in men (Fukumoto et al., 2010). While the role of estrogen in BDNF expression was postulated to underlie this finding, it is notable that BDNF is correlated with cortisol (Begluiomini et al., 2008). "
    International Psychogeriatrics 08/2014; 26(10):1-6. DOI:10.1017/S1041610214001549 · 1.89 Impact Factor
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    • "For instance, a polymorphism in the promoter region of the BDNF gene (C270T) has been associated with increased risk of AD (Olin et al. 2005). As in the case of the BDNF Val66Met polymorphism, negative findings have also been reported (Akatsu et al. 2006; Fukumoto et al. 2010; Nishimura et al. 2004). Despite the controversial findings of genetic studies regarding the association between BDNF polymorphisms and the risk of AD, a large bulk of evidence suggests that a reduced neurotrophic support may play a role in ageassociated cognitive decline and AD. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF became a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer's disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Altered BDNF circulating levels have also been reported in other neurodegenerative and psychiatric disorders, hampering its use as a specific biomarker for AD. Therefore, BDNF seems to be an unspecific biomarker of neuropsychiatric disorders marked by neurodegenerative changes.
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    • "Thus, these findings suggest an interesting sexual dimorphism in the effects of BDNF genetic modifications on depression-related phenotypes. BDNF genetic variations in humans might show sex differences on cognitive components, reactivity to stress, and predisposition to psychiatric illnesses (Raz et al. 2009; Shalev et al. 2009; Fukumoto et al. 2010; van Wingen et al. 2010; Verhagen et al. 2010; Pregelj et al. 2011). Similarly, genetic BDNF disruption in mice showed sex differences, at least for parameters such as locomotor activity, stress reactivity, and anxiety-and depression-like behaviors (Monteggia et al. 2007; Autry et al. 2009). "
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    ABSTRACT: BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders.
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