Impact of brain‐derived neurotrophic factor genetic polymorphism on cognition: A systematic review

Abstract Introduction Brain‐derived neurotrophic factor (BDNF) has an important role in the neurogenesis and neuroplasticity of the brain. This systematic review was designed to examine the association between BDNF Val66Met (rs6265) polymorphism and four cognitive domains—attention and concentration, executive function, verbal fluency, and memory, respectively. Methodology Primary literature search was performed using search engines such as PubMed and Scopus. Observational studies that evaluated the neurocognitive performances in relation to BDNF polymorphism within human subjects were included in this review, while animal studies, overlapping studies, and meta‐analysis were excluded. Results Forty of 82 reviewed studies (48.8%) reported an association between Val66Met polymorphism and neurocognitive domains. The proportion of the studies showing positive findings in cognitive performances between Val/Val homozygotes and Met carriers was comparable, at 30.5% and 18.3%, respectively. The highest percentage of positive association between Val66Met polymorphism and neurocognition was reported under the memory domain, with 26 of 63 studies (41.3%), followed by 18 of 47 studies (38.3%) under the executive function domain and four of 23 studies (17.4%) under the attention and concentration domain. There were no studies showing an association between Val66Met polymorphism and verbal fluency. In particular, Val/Val homozygotes performed better in tasks related to the memory domain, while Met carriers performed better in terms of executive function, in both healthy individuals and clinical populations. Conclusion While numerous studies report an association between Val66Met polymorphism and neurocognitive changes in executive function and memory domains, the effect of Met allele has not been clearly established.


| INTRODUC TI ON
The brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin superfamily and has an essential role in the neurogenesis and neuroplasticity of the brain (Matsuo et al., 2009). The signaling BDNF supports the survival of existing neurons and encourages the proliferation and differentiation of new neurons and synapses in both the central and peripheral nervous system (Acheson et al., 1995;Huang & Reichardt, 2001). In the brain, BDNF is highly expressed in the hippocampus, cortex, and basal forebrain and has an important role in regions that are vital to learning and memory (Bekinschtein, Cammarota, & Katche, 2008).
The expression of BDNF is encoded by the BDNF gene which has numerous polymorphisms. BDNF gene encodes for the precursor polypeptide (pre-pro-BDNF) which is proteolytically cleaved to generate pro-BDNF and mature BDNF. Pro-BDNF is known to modulate neuronal structure and long-term hippocampal-plasticity (Bath & Lee, 2006;Binder & Scharfman, 2004). The most extensively studied single nucleotide polymorphism (SNP) in the BDNF gene is the G196A polymorphism (rs6265). The G196A polymorphism occurs in the proregion of BDNF, resulting in an amino acid substitution of valine for methionine at codon position 66 (Val66Met). This polymorphism change has been linked to aberrant sorting of pro-BDNF into secretory vesicles and decreased activity-dependent secretion of BDNF which constitutes the main process in the regulation of extracellular levels of BDNF (Wei et al., 2012). There has also been suggestion by a study that this polymorphism may influence the interaction between mature and pro-BDNF, affecting the stability of the complex formed between the two and attenuating the ability of BDNF to inhibit hippocampal long-term depression (Uegaki et al., 2017).
In view of the importance of BDNF in the central nervous system (CNS) and the functional consequences of its SNP, numerous genetic studies have evaluated the association between the BDNF rs6265 polymorphism with cognitive performance in various disease states.
Recent studies have also focused their interest in implications of BDNF on the pathogenesis of brain-related disorders such as neurodegenerative and psychiatric diseases (Adachi, Numakawa, Richards, Nakajima, & Kunugi, 2014;Yang, Ren, Zhang, Chen, & Hashimoto, 2017). As BDNF is highly expressed in regions of the CNS that modulate learning and memory, it would be of interest to understand how the BDNF rs6265 polymorphism influence specific cognitive domains such as the attention and concentration, executive function, verbal fluency, and memory. Therefore, this systematic review was conducted to evaluate the relevant studies regarding associations between the SNP Val66Met and neurocognitive domains.

| Literature search strategy
A systematic primary literature search was conducted using PubMed and Scopus in July 2015. The search included articles published exclusively in English dated up to 1 May 2017. No screening limits were imposed in terms of the publication dates. The literature search was performed using Medical Subject Headings and from combinations of relevant keywords, such as "BDNF," "brain-derived neurotrophic factor," "Val66Met," "polymorphism," and "neurocognition".
Bibliographies of relevant articles were also reviewed.

| Inclusion/exclusion criteria
Published studies were included into the systematic review if they fulfilled the following inclusion criteria: (a) evaluated cognitive performance in relation to the BDNF rs6265 polymorphism in either a healthy population or a specific clinical population, (b) reported the allele and genotype distribution in the study population, and (c) utilized traditional neuropsychological batteries to assess cognitive function.
In vitro research, animal research, editorials, systematic reviews, and meta-analysis were excluded. Studies were also excluded if the Mini Mental State Examination (MMSE) and Intelligence Quotient (IQ) have been used to evaluate cognitive performance in the human population. This is because MMSE not only lacks sensitivity in identifying mild cognitive impairment, but the scores are also influenced by demographic factors such as age, education, cultural, and socioeconomic background. Conversely, studies utilizing IQ test as an outcome were excluded because IQ test is not a comprehensive method for evaluating the various cognitive domains. Studies that utilized functional magnetic resonance imaging (fMRI) as the sole outcome to measure brain functioning were also excluded.

| Data extraction
Three investigators independently extracted the data using a predesigned, piloted form. Each study was reviewed, and the relevant information was extracted and compiled. The following information was extracted from each study: study objectives, study design, study population characteristics (disease states, age, gender, and education level), total number of study participants, genotype distribution, and the type of outcome measures.
The review was carried out to evaluate the effect of Val66Met polymorphism on four cognitive domains: (a) attention and concentration, (b) executive function, (c) verbal fluency, and (d) memory.
The attention and concentration domain determine the content of consciousness and influence the quality of conscious experience, while the executive function domain represents the ability to reason, plan, and execute. Verbal fluency domain is related to verbal functioning, which involves the semantic and phonemic fluency.
Memory encompasses a broad domain which includes declarative memory tasks for verbal tasks, associative memory as well as working memory that can be used for arithmetical processing.
Among the reviewed studies, four studies (17.4%) (Kim et al., 2016;Narayanan et al., 2016;Szabo et al., 2013;Zhang et al., 2012) observed significant positive association between BDNF Val66Met polymorphism and the attention/concentration domain. In a study conducted in patients with mild traumatic brain injury, Val/Val homozygotes were reported to perform better in domains of attention/ F I G U R E 1 Flow chart of the inclusion and exclusion process of the study Search strategy: "BDNF" AND "Val66Met" AND "polymorphism" or "BDNF" AND "Val66Met" AND "neurocognition" concentration over time (Narayanan et al., 2016). Conversely, Met carriers were reported to perform better than Val/Val homozygotes in attention/concentration domain in another study focusing on elderly population with cardiovascular diseases (Szabo et al., 2013).

Val homozygotes have significantly better executive function than
Met carriers in healthy adults and populations with Parkinson's disease, traumatic brain injury, obsessive-compulsive disorder, and bipolar disorder.

| Verbal fluency domain
Eighteen studies were identified when evaluating BDNF Val66Met

| D ISCUSS I ON
The various types of memory would require an independent measure of their own and are likely to be influenced by BDNF polymorphism to varying extents. In order to make reliable and reasonable comparisons across studies, the measures for memory tests could have been standardized or be matched to a defined memory.
To illustrate our point, while one study reported findings that Val/ Val homozygotes were found to perform better in spatial memory compared to the other genotypes, they scored worse on measure of visual memory (Yogeetha et al., 2013). In another study looking at schizophrenia population, genotypes of Val/Val homozygotes were found to have better verbal memory and logical episodic memory (Zhang et al., 2012). While it appears that Val66Met polymorphism confers better verbal memory, it is noteworthy that our reviewed studies did not show an association with verbal fluency (Table 1).
This indicates that there may be some specificity of association of Val66Met polymorphisms with the respective cognitive domains.
Another objective measure worth exploring as a basis of comparison across studies is to conduct neuroimaging analysis such as fMRI to assess actual neural activation in brain activity. A metaanalysis conducted found no significant association between BDNF Val66Met polymorphism and hippocampal volumes in healthy humans, with hippocampal volumes being of interest because it is a well-established brain region that has an important role in learning and memory. However, the findings observed that Met carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (Harrisberger et al., 2014). Given the current advancement in neuroimaging techniques, it might be worth looking at the exact brain 1 Counted as proportion of studies out of total unique studies favoring regions that are activated when correlating with cognitive function.
This would enhance our mechanistic understanding behind the biological mechanism.
With regards to the attention/concentration domain, it was interesting to note that positive associations were identified only in cohorts with specific disease states. The findings from one study favors Met carriers, suggesting that Met allele favorably interacts with cognitive changes associated with the cardiovascular disease or that cardiovascular diseases may have affected circulating levels of BDNF, given that BDNF is permeable to the blood-brain barrier (Szabo et al., 2013). Another study finds that Met carriers, regardless of whether they were healthy controls or schizophrenic, performed worse than genotypes of Val/Val homozygotes in the attention/concentration domains (Zhang et al., 2012). It is postulated that hippocampal neurons that contain Met allele showed less depolarization-induced BDNF secretion, resulting in reduced activity-dependent BDNF release and poorer hippocampalmediated function (Zhang et al., 2012).
In reviewing the studies on the domain of executive function do-  (Egan et al., 2003;Rybakowski et al., 2003Rybakowski et al., , 2006Tan et al., 2005;Zhang et al., 2012). In some instances, poorer neurocognition could be attributed to neurodegenerative diseases itself rather than BDNF polymorphism, confounding the actual extent of effect from the BDNF genotype. Disease states which affect cognitive function may mask or worsen the effect of genetic polymorphism on cognition.
While BDNF polymorphism was not significantly associated with serum BDNF, this polymorphism is believed to influence intracellular sorting of BDNF, resulting in decreased synaptic plasticity (Bath & Lee, 2006;Binder & Scharfman, 2004). The biological function of pro-BDNF is also not limited in being an inactive precursor with some suggesting that it may have an antagonistic effect (Bath & Lee, 2006;Binder & Scharfman, 2004). The overall physiological functions may be better correlated by a balance of both pro and mature BDNF, so measuring BDNF as a ratio of pro: mature forms might be a more accurate reflection of BDNF effect in relation to brain disorders. There are also variations attributed to the source of BDNF as levels differ from plasma to serum samples. Our study posits that, without the direct quantification of circulating BDNF, it might be difficult to evaluate the association between BDNF genotype and cognitive function.
In a study involving patients with Alzheimer's disease, Met carriers were reported to have better executive function. It was suggested that Met carriers are protected from the hippocampus cortical atrophy or subcortical tract changes, leading to them having a decreased risk of Alzheimer's and improved performance in domain related to executive function (Nagata et al., 2012). However, it remains unclear if the hippocampal atrophy is attributed to neuropsychiatric disorders or the extent of contribution genetic polymorphism has on its effect.
Conversely, in another study targeting at patients with high level of beta-amyloid (Aβ), it was reported that there is greater hippocampal atrophy found in Met carriers. Met carriers were found to show a significant decline in executive functions compared to genotypes of Val/Val homozygotes over a 36-month period instead (Lim et al., 2013). Met carriers were also found with worse memory performance in an Alzheimer's population, with deleterious effects of Aβ on memory found to be greater in Met carriers (Lim et al., 2016). This suggests that high Aβ level might have been a necessary condition for cognitive decline in this context and that BDNF Val66Met polymorphism has a downstream moderation of the effect of Aβ in executive function. The implication of these findings is that cognitive influence of BDNF polymorphism might not necessarily be related to its effect on brain region.
Old age could also be another factor that determines the direction of effect BDNF Val66Met polymorphism has on neurocognition as aging is often accompanied by decrease in hippocampus volume which is associated with decline in episodic memory (Harrisberger et al., 2014). Some studies have demonstrated that Met carriers are more protected during aging than Val/Val homozygotes when it comes to cognitive function such as executive functions that involve the prefrontal cortex. For some aspects of memory, Met carriers were found to be performed poorly in associative memory, regardless of age. BDNF Val66Met polymorphism exerts an influence regardless of age on subjective and associative memory while may exacerbate age-related differences in prospective memory (Kennedy et al., 2015).
Children aged between 6 and 10 who are Val/Val homozygotes were found to outperform Met carriers on tasks that have a strong memory component and exert lesser effort in neural activation compared to Met carriers on fMRI analysis (Jasinska et al., 2016). Yet in another study examining the influence of BDNF Val66Met polymorphism on behavioral outcome of healthy young adults between 20 and 30 years old, Met carriers tend toward better performance. It is implied that the polymorphism can be an advantage or a disadvantage depending on the tasks examined as each genotype use slightly different brain activation pattern as some performance-related tasks may be more dependent on BDNF (Dennis et al., 2011) to the argument for preemptive scanning to be carried out at the affected brain regions. Our reviewed studies also suggest that the influence of genetics on cognition could become more apparent under certain disease states or aging. While Met allele is hypothesized to negatively affect intracellular trafficking and activitydependent secretion of BDNF and is expected to cause poorer neurocognition performance, there is also an interplay of factors between gene, environment, and disease state in determining the direction of effect. For instance, there has been a cross-sectional study which found that the association between physical activity and episodic memory was mediated by BDNF polymorphism, as Val/Val homozygotes were found to perform significantly better than Met carriers if they were active in physical activity, showing how that environmental factor can also be a consideration (Canivet et al., 2015).
Overall, consolidated results from our reviewed studies showed that BDNF polymorphisms' relationship with cognition might be more complex than previously thought. More future studies could delve into the correlation between the gene loci and cognitive domains.

| CON CLUS ION
Across the four domains that were studied, approximately half of the identified studies reported an association between Val66Met polymorphism with neurocognitive domains. In particular, Val/Val homozygotes performed better in tasks related to the memory domain.
On the other hand, Met carriers appear to give rise to improved neurocognitive performances in terms of executive function. The results from the studies focusing on the domain of verbal fluency and attention/concentration were less conclusive. While more studies might be needed in the future with a more clearly defined cohort and comorbidities being adjusted for, our findings suggest that Val66Met polymorphism may be associated with the cognitive domains of executive function and memory domains although the effect of Met allele remains to be clearly established. More consistent replicated findings of the Val66Met polymorphism with neurocognition are required in the future to extend its clinical relevance.

CO N FLI C T O F I NTE R E S T
None declared.