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: 3.42). 01/2009; 153B(1):235-42. DOI: 10.1002/ajmg.b.30986
Source: PubMed


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). "

    Full-text · Article · Aug 2014 · International Psychogeriatrics
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    • "A large study consisting of 16 research centers worldwide (including 4,711 patients and 4,537 controls) reported that the Met66 allele of Brain Derived Neurotrophic Factor (BDNF) gene, which reduces the transport of BDNF, is associated with an increased risk of AD in women (odds ratio =1.14, 95% confidence interval 1.05–1.24, P=0.002), but not in men.97 This finding is biologically plausible since estrogen plays an important role in the expression of BDNF.98 Postmenopausal women with the MET66 allele would therefore have both reduced transport and expression of BDNF, thus causing an increased risk of AD. "
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    ABSTRACT: With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD.
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    • "BDNF genotype by sex interactions are also found for disease vulnerability. Recently, Fukumoto et al. (2010) found that elderly female Met-carriers are more vulnerable to developing Alzheimer's disease in the later stages of life compared with males and Val-homozygous females. BDNF genotype also seems to be a risk factor for developing depression, in this case, specifically in men (Verhagen et al. 2010). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays a critical role in brain development. A common single nucleotide polymorphism in the gene encoding BDNF (rs6265, Val66Met) affects BDNF release and has been associated with altered learning and memory performance, and with structural changes in brain morphology and corpus callosum integrity. BDNF Val66Met has more recently been shown to influence motor learning and performance. Some of the BDNF effects seem to be modulated by an individual's sex, but currently the relationship between BDNF and sex in the motor domain remains elusive. Here, we investigate the relationship between BDNF Val66Met genotype and an individual's sex in the motor system. Seventy-six healthy, previously genotyped, individuals performed a task in which the participant drew lines at different angles of varying difficulty. Subjects controlled the horizontal and vertical movement of the line on a computer screen by rotating two cylinders. We used this bimanual motor control task to measure contributions from both current motor function and the pre-existing interhemispheric connectivity. We report that BDNF genotype interacts with sex to influence the motor performance of healthy participants in this bimanual motor control task. We further report that the BDNF genotype by sex interaction was present in the more difficult trials only, which is in line with earlier findings that genetic effects may become apparent only when a system is challenged. Our results emphasize the importance of taking sex into account when investigating the role of BDNF genotype in the motor system.
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