How to Interpret The Information
You have to understand how to view genes. There’s often contradictory studies, but the important thing is to see how the gene functions and what role the gene product plays in the body.
So whether having genes for high BDNF production results in better spatial memory or not isn’t the point. The point is that BDNF plays a role in memory and if you have a low BDNF producing genes you probably want to raise it. But also be aware of the drawbacks.
Introduction to BDNF and How to Increase It
The BDNF Gene Rs6265
Get your 23andme and find out what your genotype is.
The SNP is called “rs6265″…I’m heterozygous (C;T), which means I’m not a normal producer. As you’ll see, this is usually not good. FML.
The T allele ranges from 0% in Africa, 17% of whites, 60% in Asia (R).
Between 60-65% of the white population has CC. Less than 30% of the Chinese have CC. About 90% of the black population has CC, and some Africans have about 98% CC (Yoruba).
Some key points:
On your 23andme report you should see “CC”, “CT” or “TT”, but the research papers talk about “G” and “A”.
- “G” is equivalent to “C” and “A” is equivalent to “T”.
- G is the more common allele and A is less common.
- The variation is known as “Val66Met”
- G or C=”Val”
- A or T=”Met”
- A or T or “Met” decreases BDNF (R, R2).
What Happens When You Have A “T” Allele?
“T” allele carriers had lower blood BDNF than CC (R).
The presence of the T allele modifies the distribution of BDNF in the cell, it’s processing, and secretion in rat hippocampal neurons when compared to cells expressing the C allele (R).
The T allele results in a more scattered BDNF in cell bodies, whereas CC is more concentrated in granules in the dendrites (branchy spines of the neuron) which get secreted (R).
Additionally, the T allele results in less secretion of BDNF. Studies with human subjects corroborated that the T allele is associated with less of a hippocampal response and impaired neuronal integrity/synaptic activity (R).
The T allele had less encoding-related brain activity in the bilateral hippocampi and right parahippocampal gyrus (R).
The T allele was shown to be associated with abnormal packaging of the precursor of BDNF and decreased mature BDNF production in cells (R).
The Benefits of CC
- CC has about 20 minutes more Slow wave sleep (stage 3/4) and increased sleep intensity compared to CT (and presumably more than TT, but it wasn’t studied). The difference was most pronounced in the first slow wave sleep episode. This holds whether subjects are sleep deprived or not. By contrast, superficial stage 2 sleep was reduced in CC (R).
- CC showed better response accuracy than “T” on a verbal 2-back working memory task (R).
- CC vs TT+CT had 19.3 vs 17.0 of BDNF, not too significant of a difference (R). But, other factors of BDNF are also altered.
- CC had double the alpha waves in wakefulness compared to CT. CC had higher alpha, theta, and sigma waves in REM sleep (R).
- In Chinese, CC had higher performance in digital working memory and spatial localization than TT (R).
- CC had higher mean intelligence (R).
- CC respond better to repetitive transcranial magnetic stimulation, with drug-resistant depression (R).
- CC preferentially sought positive emotions (e.g., happy faces) and had a stronger reaction to negative emotions (e.g., angry, fearful, and sad faces) compared to CT (R).
- Airplane Pilots with a “T” allele had their scores on flight simulations drop twice as fast than those without the T allele. BDNF and NAA levels dropped significantly more in people with the T allele (R).
- CC (compared to TT) show reduced the stress-induced anxiety-like behavior (R). (contradictory)
Negatives of CC
- CC subjects scored higher on “trait-anxiety” and neuroticism (not significant) compare to CT or TT (R), but other studies have not found an association with Neuroticism (R).
- CC has a higher risk of depression (1.7X) (R).
- CC is a higher risk for allergies. Increased levels of BDNF in blood, lung fluid, and nose fluid positively correlate with disease activity and severity in patients with allergic rhinitis (AR), asthma and atopic eczema (R).
The Benefits of the T Allele
- TT have lower BMI compared to the two other genotypes (R).
- The T allele is associated with lower systolic blood pressure (R).
- The T allele is maybe less susceptible to degenerative neurological disorders like Parkinson’s, Huntington’s, Lupus, MS (R).
- The T allele may also be protective against depression when subjected to repeated defeat (R).
- The T allele carriers had a lower incidence of decreased sexual desire (OR = 0.32, p = 0.01) as compared to the CC (R).
- The T allele may make schizophrenia less likely. In Germans, the frequency of the CC was 65% in schizophrenia patients and 54% in patients with bipolar I disorder, and 57% in healthy subjects (R). This is contradicted by a different study, where the T allele is associated with Schizophrenia (R).
- The T allele preserves gray matter volume in MS .(R).
The Negatives of the T Allele
- The T allele possibly has decreased hippocampal volume in some cases. However, in a large cohort of healthy human subjects, T was not associated with hippocampal structure or memory performance at all (R).
- TT has more anxiety (R).
- It’s important to recognize that 2011 meta-analyses could not find any differences in intelligence (R).
- TT are more introverted, depression resistant, impaired motor skills learning.
- The T allele is associated with introversion (R, R2). Since the T allele is more common amongst Asians, it’s thought that this is part of the explanation for increased introversion amongst Asians (R).
- T maybe has impaired learning and memory.
- T has worse motor skills and is more likely to get into a car accident (R).
- T is slower in stroke-victim recoverers (R).
- The T allele makes people more likely to binge eat after dietary restriction (R).
- The T allele numerically revealed a reduced overall performance in the verbal learning memory test, but this did not turn out to be statistically significant (R).
- TT had significantly lower N-acetyl-aspartate and Glutamate metabolic ratios compared with CC. The difference between CT and CC was negligible. BDNF may exert its observed effects on NAA via its influence on the glutamate system (R).
- The CT and TT genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. TT showed a 19% increased risk of schizophrenia compared to AG (R).
- The presence of a T allele is associated with a poorer executive functioning in OCD (R).
- T=Higher Alzheimer’s risk in non-APOE4 carriers (R).
- CT was associated with both ADHD and Intellectual disability, and the C allele was significantly associated with ADHD (R).
- Depressed patients who had CT or TT showed significantly increased the risk of suicidal behavior.
- The T allele causes a higher risk of alcohol-related depression (R).
- The T allele increases bipolar risk, but T’s respond better to treatment (R).
- The T alleles recalled lower percentage of positive words in childhood (R).
- Non-significant: Meta-analysis 6% increased the risk for depression TT vs CC. 3% decreased risk comparing CT with CC genotypes (R).
- T allele carriers are particularly sensitive to Childhood adversity – The T allele had less gray matter compared to CC’s with childhood adversity.
- The T allele had higher heart disease-related depression (R).
BDNF (Rs6265) and Weight
In men, CC had twice the risk of being overweight compared to people with a “T”. The opposite was the case in women, where CC was 50% less likely to be overweight than people with a “T” allele (R).
Men with CC who consumed more PUFA (mainly omega-6, I assume) weighed less (more than 8.76% of calories) (R).
Women with CC weighed less as well when they consumed more PUFA (more than 8.76% of calories), but this wasn’t statistically significant (R).
As you can see, in CC men, BMI goes down the more PUFAs they consume. Whereas the more PUFAs that CT or TT genotypes consumed, the fatter they were.
BDNF (Rs6265) and The Stress Response
Why is this?
So BDNF in the hypothalamus stimulates the HPA axis/stress response (CRH), whereas reduced expression of BDNF decreases the stress response (CRH) (R).
Actually, cortisol shuts off the stress response through decreasing BDNF in the hypothalamus (PVN). When the cortisol receptors are broken – usually from chronic or extremely acute stress, CRH doesn’t shut down and the stress response keeps going off (R).
So cortisol isn’t shutting down the stress response because it’s not decreasing BDNF in the hypothalamus (PVN), which causes the stress response to keep going off.
So if you’re a high BDNF producer who is exposed to chronic stress, it could make your situation worse by having even more elevated BDNF levels.
BDNF maintains elevated levels of neuronal excitation in the PVN by preventing GABA signaling. So BDNF suppresses the inhibitory properties of GABA on the CRH neurons, which could lead to elevated CRH levels and even more HPA axis activation (R).
BDNF (Rs6265) and Depression
Higher or lower levels of AM cortisol is associated with depression in scientific studies.
However, only CC with higher levels of cortisol had depression, but not CT (R).
But with lower AM cortisol, CT is more susceptible to depression than CC.
We see both alleles can increase the risk for depression in different scenarios.
So for me, I have to be careful that my cortisol isn’t low or else my risk for depression is higher because I’m CT.
With a high AM cortisol of 10ng/ml, CC had close to a 95% probability of depression, whereas the T allele carriers had only a 20% chance. But when the people with T alleles had very low AM cortisol they were depressed 60% of the time vs 40% of the time with CC.
Why is this?
People with high cortisol have high CRH. If these people are also a high BDNF producer, they will not be able to shut down CRH and the HPA axis well, so they’ll have a higher level of HPA activation (R).
CRH has a number of negative effects on hormones and most importantly on the circadian rhythm.
But it gets complex because BDNF also plays some roles in combatting the effects of stress, so in some ways, these people are more resilient to stress.
The bottom line is that if you’re a high BDNF producer, your HPA axis will be more easily triggered, but BDNF will protect you in other ways against stress.
BDNF (Rs6265), EEG and Slow Wave/Deep Sleep
As mentioned above, CC has about 20 minutes more Slow wave sleep (stage 3/4) and increased sleep intensity compared to CT (R).
When awake, CC had about double the EEG alpha waves (9.75-11.75 Hz) compared to the CT genotype subjects (both in a rested and also a sleep-deprived state) (R).
In REM sleep, alpha (8.375-10.625 and 11.125-13.125 Hz), theta (6.125-7.375 Hz) and sigma (13.875-16.625 Hz) waves were higher in CC than in the T allele carriers (R).
In Non-REM sleep, EEG in the entire delta/theta range (0.125- 8.875 Hz) was consistently higher in CC compared to CT. By contrast, power was reduced in alpha (9.875-11.625 Hz) and sigma (12.375-13.625 Hz) frequencies (R).
CC had the slowest wave activity in the first slow wave cycle. However, slow wave activity tended to decline more in CC compared to CT in subsequent cycles (R).
In absolute EEG activity, there was reduced frontal beta (14.5-30 Hz) power in TT compared to CT genotypes. Standardized alpha (8-13 Hz) power was reduced in TT compared to CT or CC across all cortical regions (R).
About Alpha waves: Alpha waves can be a signal of a lapse of attention, and a recent study indicates that alpha waves may be used to predict mistakes. Because of alpha waves’ connection with relaxed mental states, an increase in alpha wave activity is a desirable outcome for some types of biofeedback training. If you can create alpha waves by will, you can fool lie detectors. Zen-trained meditation masters produce noticeably more alpha waves during meditation. (R)
About Theta Waves: In older children and adults, theta waves tend to appear during meditative, drowsy, or sleeping states, but not during the deepest stages of sleep (R).
About Delta Waves: Delta waves are mainly associated with Slow Wave Sleep or the deepest stages of non-rem sleep (R).
BDNF (Rs6265) and N-acetyl aspartate (NAA)
TT had significantly lower N-acetyl-aspartate and Glutamate metabolic ratios compared with CC. Differences between CT and CC was negligible. BDNF may exert its observed effects on NAA via its influence on the glutamate system (R).
As you can see the NAA isn’t much different between CC (val/val) and CT (val/met), but then it drops off with TT (met/met).
NAA functions as a neurotransmitter in the brain by acting on glutamate receptors.
NAA may be a marker of creativity. It has also been demonstrated that high NAA level in the hippocampus is related to better working memory performance in humans.
NAA may be a significant mechanism by which brain training enhances cognition (R).
How to increasing NAA:
- Aerobic Exercise (R)
- Lithium (R),
- EGCG (R)
- DHA adequacy (R)
- Ketogenic diet (R) (NAA recovery from injury)
- Creatine (R) (prevents decrease in late stage in ALS)
- tDCS (R)?
What decreases NAA:
- Meditation decreases NAA in the left thalamus (R).
- Rats with Generalized Anxiety Disorder had less NAA (R).
Other BDNF Genes
- RS11030101 (BDNF)
- RS11030104 (BDNF)
- RS12273363 (BDNF)
- RS12273539 (BDNF)
- RS2049046 (BDNF)
- RS56164415 (BDNF)
- RS6265 (BDNF)
- RS7103411 (BDNF)
- RS8192466 (BDNF)
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