rs6265 — BDNF Val66Met

BDNF Val66Met — The Neuroplasticity Variant

Brain-derived neurotrophic factor¹¹ Brain-derived neurotrophic factor
BDNF is the most abundant neurotrophin in the adult brain. It belongs to the nerve growth factor family and signals through the TrkB receptor to promote neuronal survival, differentiation, and synaptic plasticity (BDNF) is the brain's master growth signal for neurons. It drives the formation of new synaptic connections, strengthens existing ones, and supports neuronal survival across the lifespan. The Val66Met variant (rs6265) is the most studied polymorphism in all of neurogenetics — a single amino acid change that alters how BDNF is released from neurons, with measurable consequences for memory, brain structure, stress resilience, and response to exercise.

The Mechanism

BDNF exists in two secretory pools inside neurons. The constitutive pathway²² constitutive pathway
A steady, low-level release of BDNF that occurs regardless of neuronal activity, maintaining baseline trophic support provides a steady trickle of BDNF. The regulated pathway³³ regulated pathway
Activity-dependent release triggered by neuronal firing, essential for long-term potentiation (LTP) and memory consolidation. This is the pathway impaired by the Met allele releases BDNF in bursts when neurons fire — and this activity-dependent release is what drives long-term potentiation⁴⁴ long-term potentiation
LTP: the molecular basis of learning and memory. When neurons fire together repeatedly, their connections strengthen. BDNF is a key mediator of this process, memory consolidation, and synaptic remodeling.

The Val66Met substitution occurs in the prodomain⁵⁵ prodomain
The "pro" region of the BDNF precursor protein (pro-BDNF), which is cleaved before secretion. The prodomain contains the sorting signal that directs BDNF to secretory granules of the BDNF precursor. The methionine substitution disrupts a critical sorting signal⁶⁶ methionine substitution disrupts a critical sorting signal
Chen ZY et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci, 2004 that directs pro-BDNF into secretory granules. Met-BDNF is not properly sorted into these granules, so it cannot be released in the activity-dependent bursts that neurons need for plasticity. Total BDNF production is normal — but the regulated release that matters for learning and memory is impaired by roughly 18-30% in heterozygotes and more substantially in Met/Met homozygotes.

The Evidence

The landmark 2003 study by Egan and colleagues⁷⁷ landmark 2003 study by Egan and colleagues
Egan MF et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 2003 established the core finding: Met carriers showed reduced hippocampal activation during memory tasks and poorer episodic memory performance. This was confirmed by Hariri et al.⁸⁸ Hariri et al.
Hariri AR et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci, 2003, who found that the BDNF genotype-hippocampal interaction accounted for 25% of the variance in recognition memory.

A meta-analysis of 3,620 healthy subjects⁹⁹ meta-analysis of 3,620 healthy subjects
Molendijk ML et al. A systematic review and meta-analysis on the association between BDNF val66met and hippocampal volume. Am J Med Genet B Neuropsychiatr Genet, 2012 found Met carriers have modestly smaller hippocampal volumes (Cohen's d = 0.13, P = 0.02). The effect is real but small — and likely influenced by age, with some evidence that differences become more pronounced in older adults and in the context of neuropsychiatric illness.

The stress connection is equally important. The Met allele is associated with heightened HPA axis reactivity¹⁰¹⁰ heightened HPA axis reactivity
The hypothalamic-pituitary-adrenal axis is the body's central stress response system. Heightened HPA reactivity means a stronger cortisol response to stressors to psychological stress, and a meta-analysis of gene-environment interaction¹¹¹¹ meta-analysis of gene-environment interaction
Hosang GM et al. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med, 2014 found that the Met allele significantly moderates the relationship between life stress and depression (P = 0.01 for stressful life events). In men specifically, the Met allele was associated with increased depression risk (OR 1.27, 95% CI 1.10-1.47).

Exercise — The Most Powerful BDNF Booster

Aerobic exercise is the strongest known stimulus for BDNF release. The Erickson et al. randomized controlled trial¹²¹² Erickson et al. randomized controlled trial
Erickson KI et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA, 2011 demonstrated that one year of moderate aerobic walking increased hippocampal volume by 2% and significantly raised serum BDNF in 120 older adults — effectively reversing 1-2 years of age-related hippocampal shrinkage.

The relationship between Val66Met and exercise response is nuanced. A systematic review¹³¹³ systematic review
Helm EE et al. The BDNF Val66Met polymorphism, regular exercise, and cognition: a systematic review. Exerc Sport Sci Rev, 2020 found that exercise benefits cognition regardless of genotype. Some studies suggest Val/Val carriers show greater BDNF increases after acute exercise, while others find Met carriers may derive larger cognitive benefits from regular exercise programs — potentially because they have more room to improve in activity-dependent BDNF signaling. The practical takeaway: regular aerobic exercise is beneficial for everyone, and may be especially important for Met carriers who start with reduced activity-dependent BDNF release.

Practical Implications

The Val66Met variant is not a disease-causing mutation. Roughly 36% of people worldwide carry at least one Met allele, and the majority function normally. The variant modestly shifts the curve on memory efficiency, stress resilience, and hippocampal integrity — effects that are most relevant when combined with aging, chronic stress, or sedentary lifestyle.

The actionable finding is clear: lifestyle factors that boost BDNF signaling — particularly aerobic exercise, quality sleep, and stress management — can compensate for reduced activity-dependent release. Met carriers who exercise regularly may effectively normalize their BDNF signaling, while sedentary Met carriers are at greatest disadvantage.

Interactions

BDNF and COMT (rs4680)¹⁴¹⁴ COMT (rs4680)
Catechol-O-methyltransferase: the enzyme that breaks down dopamine in the prefrontal cortex. The Met158 variant (rs4680 AA) has lower enzyme activity, leading to higher dopamine levels both influence prefrontal cortex function through converging dopamine-BDNF pathways. A review of the molecular genetics of cognition¹⁵¹⁵ review of the molecular genetics of cognition
Savitz J et al. The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav, 2006 highlighted that BDNF promotes survival and function of dopaminergic neurons, while COMT determines dopamine clearance in prefrontal cortex. Carriers of both BDNF Met and COMT Met (rs4680 AA) may have a specific prefrontal vulnerability that benefits particularly from combined exercise and stress management strategies.

BDNF also interacts with the serotonin system. The Val66Met variant has been shown to interact epistatically with 5-HTTLPR¹⁶¹⁶ interact epistatically with 5-HTTLPR
Grabe HJ et al. BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. Neuropsychopharmacology, 2009 to influence neuroticism and stress vulnerability, though 5-HTTLPR is a variable-length repeat rather than a single SNP.

The Val66Met variant may modulate response to antidepressant treatment. Met carriers show different response patterns to SSRIs depending on ethnicity, and the Met allele appears to impair the synaptogenic and antidepressant effects of ketamine¹⁷¹⁷ impair the synaptogenic and antidepressant effects of ketamine
Liu RJ et al. BDNF Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry, 2012 in preclinical models.