BDNF

What is BDNF?

Brain Derived Neurotrophic Factor is produced by neurons and regulates synaptic transmission in the hippocampus. It promotes neurogenesis and nerve growth. Because it plays a critical role in neuronal survival, synaptic plasticity and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of Alzheimer’s Disease. BDNF serum values increase in the early stages of AD, which might reflect compensatory repair, however, it decreases as the disease progresses. BDNF might also explain some of the increased risk of AD in women.

BACKGROUND ON BDNF IN AD

BDNF and synaptic plasticity, cognitive function, and dysfunction. (2014, Abstract)

Converging evidence now strongly suggest that deficits in BDNF signaling contribute to the pathogenesis of several major diseases and disorders such as Huntington's disease, Alzheimer's disease, and depression. Thus, manipulating BDNF pathways represents a viable treatment approach to a variety of neurological and psychiatric disorders.

Brain Derived Neurotrophic Factor: a novel neurotrophin involved in psychiatric and neurological disorders. (2012, Abstract)

BDNF may be the "missing-link" that mediates the interaction between gene and environment, synaptic plasticity and apoptosis and transgenerational transmission of disease vulnerability. There is theoretical and empirical support for a model in which BDNF underpins the integrity of the central nervous system and this may herald a quantum leap in the way we approach disorders of the mind and brain. Understanding and developing therapies centered on the role of BDNF may lead to paradigm shifts in current practice and treatment of psychiatric and neurological disorders.

Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia (2014, Full text)

Brain-derived neurotrophic factor (BDNF) may explain some of the variation in dementia risk, and because it is inducible by factors such as reduced caloric intake3 and increased physical activity it is thought to mediate the association between healthy lifestyle and successful aging. In animal models, BDNF is highly expressed and widely distributed throughout the central nervous system especially in the hippocampus and cerebral cortex and is important in the survival and function of hippocampal and cortical, as well as cholinergic and dopaminergic, neurons. In addition, BDNF is critical for synaptic plasticity and memory processing in the adult brain.

Evidence

The effects of genetics - it’s complicated...

The most commonly studied BDNF variant is rs6265 val66met. The more common G allele encodes the Val, while the A allele encodes Met.

BDNF val66met polymorphism affects aging of multiple types of memory. (2014, Abstract)

The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory).

Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia (2014, Full text)

The absence of a significant association between BDNF SNPs and the risk for AD is not inconsistent with the association we show between serum BDNF levels and the risk for AD in women since genetic variation does not appear to explain a substantial proportion of the variation in BDNF levels. Rather, environmental factors, such as mood, diet, and physical activity,3,4 likely alter BDNF levels and BDNF may be a biological intermediate between these lifestyle factors and their impact of AD pathology and risk, a hypothesis that needs further exploration in additional studies.

HERE ARE SOME THINGS THEY DO KNOW...

Structural neuroimaging correlates of allelic variation of the BDNF val66met polymorphism (2013, Full text)

Although the val66met polymorphism does not seem to affect the activity of mature BDNF, the intracellular trafficking and activity-dependent secretion of BDNF is altered (Egan et al., 2003). At a cellular level, there appears to be a met-dose effect on intracellular localisation (Chen et al., 2004) and regulation of activity-dependent secretion of BDNF (Chen et al., 2006). Variations in n-acetyl-aspartate (NAA) levels in the hippocampus associated with the met-allele also suggest a functional met-dose effect (Egan et al., 2003).

Hippocampal investigations in BDNF are legion, and most commonly indicate a met-effect of reduced hippocampal volume (Pezawas et al., 2004), although these changes are not consistent (Koolschijn et al., 2010 and Toro et al., 2009), and have recently been suggested to be artificial due to a “winners curse” (Molendijk et al., 2012). In our analysis we did not detect an effect of genotype in the hippocampus.

Common across all our findings is the “U-shaped” profile, where heterozygotes are distinct from the homozygotes. Given our relative lack of insight in to the biology of the BDNF met-allele, as well as a dearth of studies examining the met-dose effect on brain structure, it is yet too early to know how to interpret these changes. However it does offer the important insight that, by grouping all met-carriers together, previous quantitative investigations may have missed an important aspect of the interaction between the met and val alleles.

Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration. (2013, Full text)

There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer's Disease-related brain imaging and cognitive markers of disease.

...Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume.

Brain-derived neurotrophic factor Val66Met polymorphism and hippocampal activation during episodic encoding and retrieval tasks (2011, Full text)

Taken together, converging results from both item and relational memory tasks suggest that the increase in hippocampal and parahippocampal gyrus activation for BDNF met allele carriers is not simply associated with task-related processing, but rather successful memory performance. The findings were strikingly similar across both encoding and retrieval stages of memory processing. These results indicate that met carriers are able to recruit MTL activity in order to support equitable memory performance. Moreover, reductions in cognitive performance are not a ubiquitous effect associated with the BDNF val66met genotype of these individuals or group differences in MTL volume. These findings, combined with that of previous studies also underscore the variability in results across fMRI studies attempting to measure complex cognitive functioning.

Gender-related association of brain-derived neurotrophic factor gene 196A/G polymorphism with Alzheimer's disease-a meta-analysis including 6854 cases and 6868 controls. (2014, Abstract)

Epidemiological studies have evaluated the associations between brain-derived neurotrophic factor (BDNF) 196A/G gene polymorphism and Alzheimer's disease (AD) risk. However, the results remain inconclusive. Sexually dimorphic effect of the polymorphism of BDNF 196A/G in AD patients had been proposed previously, specifically in female group. As more cases were reported, therefore, we performed a meta-analysis of published case-control studies to better understand these results. We systematically searched online databases of Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and meeting abstracts. Review Manager (Version 5.2.4) and Stata software (Version 12.0) were used for statistical analyses. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. A total of 23 publications including 25 studies were identified and entered the analysis. No significant association was observed in overall population, as well as subgroups stratified by ethnicity (Caucasian and Asian). However, when stratified by gender, significant association was observed just in female subgroup (A allele vs. G allele: OR = 1.15, 95% CI = 1.06-1.25; A/A vs. G/G: OR = 1.29, 95% CI = 1.06-1.57; A/A + A/G vs. G/G: OR = 1.30, 95% CI = 1.11-1.53). This meta-analysis confirmed the gender-related association between BDNF 196A/G polymorphism and AD risk, which may indicate a certain effect of female hormone on progression of the disease. Larger sample size and more studies with homogeneous AD patients and well-matched controls are needed in future.

Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis. (2010, 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.

Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study (2014, Full text)

During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95%CI, 0.28–0.85; P = .01; and hazard ratio, 0.46; 95%CI, 0.24–0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95%CI, 0.50–0.85], P = .001; 0.63 [95%CI, 0.47–0.85], P = .002; and 0.27 [95%CI, 0.11–0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.

LINKS TO DEPRESSION, AGING, and OTHER FACTORS

Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. (2014, Abstract)

Changes in brain-derived neurotrophic factor (BDNF) level are implicated in the pathophysiology of cognitive decline in depression and neurodegenerative disorders in older adults...The present results suggest that aging is an important factor related to decline in BDNF level.

Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. (2014, Abstract)

A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus.

Apathy and APOE4 are associated with Reduced BDNF Levels in Alzheimer's Disease. (2014, Abstract)

These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers.

Proposed mechanism(s)

BDNF mediates adaptive brain and body responses to energetic challenges. (2014, Abstract)

By stimulating glucose transport and mitochondrial biogenesis BDNF bolsters cellular bioenergetics and protects neurons against injury and disease. By acting in the brain and periphery, BDNF increases insulin sensitivity and parasympathetic tone. Genetic factors, a 'couch potato' lifestyle, and chronic stress impair BDNF signaling, and this may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes, and neurological disorders.

Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons. (2013, Full text)

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.

Dysregulation of Neurotrophic and Haematopoietic Growth Factors in Alzheimer’s Disease: From Pathophysiology to Novel Treatment Strategies (2014, Full text) - click on download to see full article

But may not be a good marker to test on its own...

Neuroinflammation and Brain Functional Disconnection in Alzheimer’s Disease (2013, Full text)

Activated T lymphocytes can nevertheless also mediate neuroprotection and promote neurogenesis by secreting BDNF. BDNF production was increased in aMCI; these results are is in line with data showing higher BDNF serum levels in preclinical stages of Alzheimer’s disease (Laske et al., 2006; Angelucci et al., 2010) and with post-mortem examinations of AD brains indicating a significant increase of BDNF concentration in hippocampus and parietal cortex (Durany et al., 2000) and of its receptor TrkB in astrocytes and senile plaques (Connor et al., 1997).


The Associations between Serum Brain-Derived Neurotrophic Factor, Potential Confounders, and Cognitive Decline: A Longitudinal Study (2014, [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966768/� Full text])

Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline.