Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease

Abstract

Genes known to contribute to the genetic predisposition to Alzheimer's disease (AD) are active in pathways of neurodegeneration but explain only a minority of the genetic contribution to AD. A protein of importance in cerebral neurodegeneration is the brain-derived neurotrophic factor (BDNF). Variations in two single-nucleotide polymorphisms (SNPs) within the BDNF gene have previously been associated with AD, and one of these SNPs has also been associated with memory loss and affective disorders. We performed a case control study of three BDNF SNPs in 250 neuropathologically confirmed cases of AD and 194 unrelated controls. We did not find a significant association between the three BDNF SNPs studied and AD when evaluated individually or with haplotype analysis. Nor did BDNF genotype appear to affect the APOE epsilon4 association with AD. The three SNPs studied were closely linked (D' = 0.99 across the region). We discuss possible reasons for our failure to confirm the previously reported associations.

Association of BDNF and BCHE with Alzheimer's disease: Meta-analysis based on 56 genetic case-control studies of 12,563 cases and 12,622 controls

“…Previous studies have reported five positive results (12-16) and 21 negative results (19,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) between the BDNF Val66Met polymorphism and AD. In the present meta-analysis, no significant association was found between BDNF Val66Met and AD (P>0.05, Table II).…”

“…Heterozygous carriers of the T-allele tend to have a higher risk of developing AD than non-carriers (36). There have been a total of four significant results (13,(17)(18)(19)) and 14 non-significant results (28)(29)(30)(31)(34)(35)(36)(37)40,41,(43)(44)(45) among the previous association studies between the BDNF C270T polymorphism and AD. In the present meta-analysis, the BDNF C270T polymorphism was found to increase the risk of AD by 88% in Asians under the dominant model.…”

“…For BDNF Val66Met, there have been five positive results in Europeans (12)(13)(14)(15) and Asians (16), and 21 negative results (among 18 studies) in Europeans (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37), Asians (19,(38)(39)(40)(41)(42) and Africans (29). For BDNF C270T, there have been four positive results in Europeans (13,17) and Asians (18,19) and 14 negative results in Europeans (28)(29)(30)(31)(34)(35)(36)(37)(43)(44)(45), Asians (40,41) and Africans (29). For BCHE-K variants, there have been six positive results in Europeans (46-51) and 22 negative results in Europeans (5,(52)(53)(54)(55)…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Given the decline in BDNF in AD, the potential specificity of the decline in BDNF to temporal structures like hippocampus, and the decline in estradiol in women with age (and of course complete loss of serum estradiol after menopause), one logical hypothesis is that Alzheimer's disease is due to the reduction of estrogen-induced BDNF synthesis in hippocampus. Indeed, genetic studies to date do not provide robust evidence that there is a genetic component (a contribution of BDNF polymorphisms to the disease [126][127][128][129][130]), suggesting estrogen-BDNF interactions may be intact, but there simply may be too little estrogen to adequately maintain BDNF levels, leading to reduced signaling. This hypothesis is supported by the evidence that estradiol administration restores cognitive function in ovariectomized animals and in animal models of AD [124].…”

The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills

“…BDNF levels are decreased in Alzheimer's disease (AD) [30][31][32][33] and, interestingly, the Val not the Met allele has been associated with increased risk of AD. 34,35 Other studies have failed to replicate such an association [36][37][38][39][40] and a recent study suggested that homozygosity for the Val allele is protective against AD in female subjects. 41 As AD is characterized by memory and other cognitive deficits, genes associated with the disease are also good candidates for association with non-pathological cognitive aging.…”