Brain-derived neurotrophic factor Val66Met polymorphism and remission after antidepressant treatment in depressed Caucasian patients: a meta-analysis.

BDNF Val66Met polymorphism is linked to elevated levels of serotonin-transporter in the medial prefrontal cortex but not to altered eating behavior.

The role of neurotransmitter systems in the pathology and management of psychiatric disorders is well documented. Targeting these systems has remained the mainstay of standard pharmacological interventions, with typical and atypical antipsychotics demonstrating effectiveness in reducing both positive and negative symptoms of schizophrenia. However, their clinical efficacy and side effect profiles vary among individuals due to genetic differences.This review aims to examine key genetic variants in the dopaminergic neurotransmitter system that influence antipsychotic response, with particular emphasis on clinically relevant single-nucleotide polymorphisms (SNPs), to support improved treatment outcome prediction and precision psychiatry.Polymorphisms in genes encoding dopamine receptors, transporters, and metabolising enzymes have been associated with variability in antipsychotic efficacy and susceptibility to adverse effects. Across multiple studies, the catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and the dopamine D2 receptor/ANKK1 Taq1A (rs1800497) variant are among the most consistently reported genetic contributors to variability in dopamine signalling, receptor availability, and drug metabolism. These variants have been linked to differential therapeutic outcomes, including improved response in some treatment-resistant patients, as well as an increased risk of extrapyramidal symptoms, hyperprolactinaemia, and metabolic disturbances. These findings indicate that genetic variation in the dopaminergic system is a key contributor to differences in antipsychotic response. Integrating pharmacogenomic information in clinical practice may enhance personalised treatment strategies, reduce trial-and-error prescribing, and improve long-term outcomes in schizophrenia.

Brain-derived neurotrophic factor (BDNF) has been implicated in the neurobiology of suicide, but findings remain inconsistent. We examined studies comparing BDNF-related measures in individuals who died by suicide and non-suicide controls. ISI Web of Science, Scopus, and Embase were searched from inception through to 31 July 2025 in accordance with PRISMA guidelines. Twenty studies met inclusion criteria. Most analysed postmortem brain tissue, while fewer investigated plasma, whole blood, or cerebrospinal fluid. Postmortem studies frequently reported reduced BDNF protein and/or mRNA expression in frontal and limbic regions. Several also described increased promoter methylation. In contrast, peripheral findings were heterogeneous, and studies of the Val66Met polymorphism did not demonstrate consistent associations with suicide. Overall, evidence supports region-specific alterations of central BDNF signalling in suicide, whereas peripheral and genetic findings remain inconclusive. Methodological variability across studies limits comparability. Larger investigations using standardised protocols are needed to clarify the role of BDNF in suicide mortality.

This study analyzed the influence of the COMT Val158Met polymorphism (genotypes AA, AG, GG) on heart rate variability (HRV), psycho-emotional state, and susceptibility to sports burnout in 100 male athletes (49 soccer players and 51 track-and-field athletes) aged 17–20 years from a specialized sports school, each with at least one year of regular training experience. Among athletes with the AA (Met/Met) genotype, resting heart rate was 9.6% higher (p<0.05) compared to the GG (Val/Val) group, while SDNN and RMSSD values were 22.4% and 32.5% lower, respectively (p<0.05). In addition, AA carriers showed a 17% (p<0.05) higher level of anxiety and a greater risk of emotional exhaustion (ABQ) compared to the GG genotype. The AG (Val/Met) genotype occupied an intermediate position, demonstrating moderate stress tolerance and balanced HRV parameters. The novelty of this work lies in the comprehensive analysis of COMT Val158Met, HRV indicators, and psycho-emotional status (anxiety, stress, and burnout) in athletes of different specializations and types of higher nervous activity, a topic not previously explored in such detail. Our findings indicate that the COMT Val158Met polymorphism substantially affects autonomic regulation and psycho-emotional resilience in athletes. The GG genotype is associated with more pronounced parasympathetic responses and lower levels of anxiety, whereas AA is characterized by heightened sympathetic activity and higher risks of stress responses and burnout. These results can be used to develop individualized training and recovery programs based on genotype to help prevent sports burnout.

This study aimed to explore whether the BDNF Val66Met polymorphism influences early cortical plasticity, as measured by TMS-EEG, and its impact on rTMS therapy response in anterior-circulation ischemic stroke, with outcomes evaluated at day 14 and day 90 post-stroke. We retrospectively analyzed 200 patients genotyped for BDNF Val66Met: Val/Val (n = 102), Val/Met (n = 79), and Met/Met (n = 19). Demographic and clinical data were collected, and each patient underwent TMS-EEG before rTMS. Neurological status (NIHSS and mRS) was assessed at day 14 and day 90 post-stroke. Plasticity was measured using the composite plasticity index, N100, P30, SICI, and ICF. Clinical endpoints included NIHSS change, responder rate, and mRS distribution. Baseline profiles were comparable across groups. The genotype distribution was consistent with Hardy-Weinberg equilibrium and comparable to that of the general population. Val/Val carriers showed the most pronounced plasticity (plasticity index: 0.22 ± 0.06 vs. 0.12 ± 0.06 vs. 0.07 ± 0.06; p < 0.001). Clinically, Val/Val patients showed greater NIHSS improvement at both day 14 (ΔNIHSS: 7.4 vs. 5.3 vs. 4.9) and day 90 (8.2 vs. 6.0 vs. 5.1; p < 0.001). Responder rates were highest in Val/Val (p = 0.0045 at day 14, p = 0.0235 at day 90), with better mRS distribution (p < 0.001). The plasticity index positively correlated with ΔNIHSS (r = 0.58 at day 14; r = 0.61 at day 90; both p < 0.001) and negatively with mRS (r=-0.52; p < 0.001). The BDNF Val66Met polymorphism significantly modulates cortical excitability and functional recovery following stroke. Our findings indicate that TMS-EEG plasticity mediates the relationship between genotype and rTMS efficacy, supporting its potential as a biomarker for personalized rehabilitation strategies.

Understanding the ordinal relationships between items organized hierarchically requires constructing a rank order supporting decision-making between options. This process depends on the ability to learn reciprocal relationships and to select the best option available when making a choice. In such forms of decision-making, the prefrontal cortex (PFC) plays a crucial role in encoding the relative value of alternatives as a decision is formed. Higher-order cognitive abilities are influenced by genetic factors that affect dopamine availability in the PFC, potentially contributing to individual differences. Here, we examined the performance of 83 participants in a transitive inference (TI) task, grouped by genotype based on the Val158Met single-nucleotide polymorphism in the Catechol-O-Methyltransferase (COMT) gene. The task included a learning phase in which participants acquired the reciprocal relationships among a set of hierarchically ranked items (A > B> C > D> E > F), followed by a test phase in which they were required to compare all possible item pairs and select the higher-ranked one. While genotype did not significantly influence test-phase performance, it did affect learning efficiency. Specifically, Val homozygotes took a longer learning procedure than both heterozygotes and Met homozygotes during the learning phase. Drift diffusion modelling (DDM) revealed that task performance was explained by the efficiency of evidence accumulation, which was lower in Val homozygotes, accounting for their poorer performance not only during initial learning but also when required to switch to a reversed hierarchical structure (A < B< C < D< E < F). These findings suggest that individual differences in inferential decision-making and cognitive flexibility may be partially driven by genetically determined variations in prefrontal dopamine availability.

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the BDNF c.196G>A polymorphism (Val66Met) as a critical factor in CIPN development. Using humanized transgenic mouse models, we demonstrated that the Met66 allele of the functional Val66Met polymorphism in BDNF confers protection against oxaliplatin-induced sensory deficits, whereas the Val66 allele increases susceptibility to neuropathy. Mechanistic studies revealed that this protection operates through modulation of p75NTR-mediated signaling pathways and neuroinflammatory responses. On the basis of these findings, we evaluated two therapeutic strategies: the p75NTR modulator LM11A-31 and a compound we have developed, CN016. Both agents exhibited notable efficacy in alleviating oxaliplatin-induced neuropathy, particularly in genetically susceptible BDNF Val/Val carriers. LM11A-31 normalized neurotrophic signaling and preserved sensory structures, and CN016 effectively modulated neuroinflammatory pathways through macrophage inhibition at an optimal dose of 20 mg/kg. The BDNF Met66 variant shows about 49% prevalence in East Asian populations and 1 to 20% in other ethnic groups, suggesting population-specific susceptibility to CIPN. These findings establish BDNF genetic variation as a crucial determinant of CIPN risk and validate two promising therapeutic approaches, providing a foundation for personalized neuroprotective strategies in cancer treatment.

Background Conflicting results on the association of the Val66Met polymorphism in the BDNF gene with anxiety-related disorders are observed from previous studies and meta-analyses. We performed an updated meta-analysis to obtain more precise estimates and add additional analyses not performed by previous reviews. Methods Using combinations of various key terms, articles in PubMed, Google Scholar, and Web of Science, written in English were collected until October 31, 2024. Data were extracted independently by two authors and analyzed using Review Manager 5.4. Results Fifteen studies that are compliant with the HWE, providing a total of 14,184 participants were included in this meta-analysis after applying predefined inclusion/exclusion criteria based on study design, DSM-based diagnosis, and availability of genotype counts. Most pooled models demonstrated low to moderate heterogeneity with significant associations in the recessive model only. In the subgroup analysis, a significant effect was observed in the PD-uncategorized cohort. The Met/Met genotype demonstrated a suggestive association with increased susceptibility to panic disorder. Conclusion Our updated meta-analysis suggests that the Met/Met genotype of the BDNF Val66Met polymorphism may increase susceptibility to PD under a recessive genetic model; however, this evidence remains preliminary.

Background: Previous research has linked opioid use disorder (OUD) to neuronal reward systems and impulsivity. The aim of this study was to examine the influence of COMT rs4680 Val158Met polymorphism on impulsivity, hyperactivity and inattention (IHI) in patients with OUD. Methods: Open-label, cross-sectional cohort study was conducted involving individuals, 18 to 65 years, with OUD who either were included in opioid agonist treatment (OAT)—or same group of individuals who were awaiting induction on extended-release naltrexone (XR-NTX). Adult ADHD Self-Report Scale 18-item version was used to score IHI, and saliva samples were collected for genotyping (TaqMan assays). Logistic regression models were used to analyze the data. Results: The data of the entire cohort (n = 206) showed that carriers of one or two Val alleles had a negative association with IHI compared to Met/Met carriers (Val/Met OR = 0.43, p-value = 0.017, and Val/Val OR = 0.29, p-value = 0.005). Individuals included in OAT not waiting for XR-NTX (n = 120) exhibited the same pattern as observed in the entire cohort (Val/Met OR = 0.33, p-value = 0.019, and Val/Val OR = 0.18, p-value = 0.004), but not those who chose XR-NTX (Val/Met OR = 0.60, p-value = 0.353, and Val/Val OR = 0.47, p-value = 2.779). Conclusions: The present study revealed that individuals with OUD carrying the COMT rs4680 Val allele had lower IHI scores than Met/Met carriers. Hence, in individuals with OUD, the COMT rs4680 Met allele is associated with higher IHI symptom burden.

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort. A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models. The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ2 = 22.80, p = 1.1 × 10-5). The Met (A) allele frequency was significantly higher in patients (43.7% vs. 23.0%; χ2 = 15.84, p = 6.9 × 10-5). Unadjusted analysis showed a protective effect of GG (OR = 0.45, 95% CI: 0.24-0.82) and a markedly increased risk associated with AA (OR = 49.81, 95% CI: 2.95-839.90). Dominant carriers (GA + AA) had increased odds of MDD (OR = 2.23), and each A allele conferred a higher risk (OR = 2.60). These associations remained significant after adjustment for age and sex. The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression.

Introduction: Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson’s disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. Methods: In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Results: Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520–7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Conclusion: Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population.

Background/Objectives: The dopaminergic system regulates motivation, executive functions, motor learning, and emotional responses-processes that are key in both sport and esports. Although many studies analyse dopaminergic gene polymorphisms, their impact on psychophysical predispositions remains unclear. This narrative review aims to summarise current knowledge about the mechanisms of dopamine action and genetic determinants that may influence athletic and cognitive performance. Methods: The PubMed, Scopus, and Web of Science databases (publications from January 2010 to December 2025) were searched using keywords related to the DRD1-DRD5, COMT, SLC6A3/DAT1, and TH genes, as well as the terms 'sport' and 'esport.' Studies of athletes were included in which the relationship between dopaminergic polymorphisms and motivational and personality traits was assessed, and the results of neuroimaging and epigenetic studies were also considered. Results: Dopaminergic polymorphisms are associated with differences in reward processing, cognitive flexibility, motivation, and stress resilience. The most essential critical effects concern the DRD2 and DRD4 variants, which are associated with novelty seeking, reward dependence, and coping with stress. The COMT Val158Met polymorphism affects dopamine levels in the prefrontal cortex, modulating executive functions. The effects of individual polymorphisms are moderate, and conclusions regarding esports remain speculative due to limited research in this area. Conclusions: Dopaminergic predispositions involve interactions among genetics, neural activity, and the environment. However, current evidence is limited by small sample sizes, a predominance of European populations, scarce data on esports players, and difficulties in separating genetic effects from training-related adaptations.

Objective Brain-derived neurotrophic factor (BDNF) has been suggested to support the endurance and dopamine release of dopaminergic neurons. Its Val66Met polymorphism might modify Parkinson’s disease (PD) evolution, although evidence in Asian populations remains limited. This study aimed to explore how the BDNF rs6265 genotype is associated with the clinical characteristics and longitudinal progression patterns of PD patients in a Korean population.Methods A total of 247 patients were enrolled and followed for a mean duration of 50.9±23.9 months. Baseline and/or periodic assessments captured motor severity, nonmotor burden, cognition, orthostatic stress, cardiac denervation, and presynaptic dopamine transporter availability. The repeated measures were manipulated to infer any genotypic differences in the trajectories of each clinical domain.Results The genotype frequencies were 31.2% (77/247) for Val/Val carriers and 68.8% (170/247) for Met-allele carriers. Baseline clinical characteristics and presynaptic dopamine transporter availability were comparable between genotypes. Initially, Val homozygotes showed more preserved myocardial innervation and poorer nonfrontal cognitive performance. Longitudinal analyses demonstrated genotype-specific increases in motor and cognitive severity. Compared with Met-allele carriers, the homozygous Val group exhibited accelerated motor progression and a more rapid decline in the frontal domain after 3 years of follow-up.Conclusion The differences in myocardial denervation at diagnosis, cognitive profiles, and motor progression might suggest a potential modulatory role of BDNF polymorphisms in PD progression in the Korean population.

Post-Traumatic Stress Disorder (PTSD) is consistently linked to multidimensional working memory (WM) impairments, encompassing deficits in sustained attention, verbal and visuospatial processing, and executive control, with inhibitory dysfunction emerging as a key feature. This scoping review synthesizes evidence from 39 studies examining neurobiological mechanisms, trauma-related factors, genetic and hormonal influences, gender differences, and task-specific variability. Findings indicated that PTSD is associated with altered activation and connectivity in the prefrontal cortex, hippocampus, and related neural networks, often resulting in compensatory but inefficient recruitment patterns. Emotional distraction and comorbidities such as depression, alcohol use, and traumatic brain injury can exacerbate cognitive deficits. Performance impairments are evident across both emotional and neutral WM tasks, with visuospatial and updating processes being particularly vulnerable. Risk factors include chronic trauma exposure, older age, APOE ε4 allele, and the BDNF Val66Met (rs6265) polymorphism, while modulators such as oxytocin, cortisol, and physical activity show potential cognitive benefits under specific conditions. Methodological heterogeneity and limited longitudinal data restrict generalizability. These findings underscore the importance of early screening, targeted cognitive interventions, and inclusion of underrepresented populations to refine prevention and treatment strategies for PTSD-related WM deficits.

Objective: Genetic and environmental factors influence the expression of personality pathology and subsequent treatment efforts. This study associates genetics with a contemporary nosology of personality pathology represented in the Alternative Model for Personality Disorders (AMPD). We hypothesized traits from Criterion B of the AMPD would differ between genotypes of the catechol-O-methyltransferase (COMT) polymorphism (rs4680/Val158Met variation), given this genetic marker’s role in the metabolism of dopamine and norepinephrine, especially in the prefrontal cortex. Methods: The Personality Inventory for DSM-V (PID-5) was used to quantify personality traits, and the Genomind platform was used to identify the genotypes of the Val158Met COMT polymorphism in 84 psychiatric outpatients. Results: One of the five Criterion B personality domains and three of the twenty-five traits were significantly different among genotypes. Met/Met carriers had significantly higher pathological scores on the broad domain of negative affect and specific traits of perceptual dysregulation and separation insecurity, while the Val/Val carriers had significantly higher scores on the restricted affectivity trait. The COMT Val158Met polymorphism’s association with personality pathology was sexually dimorphic, with the two domains and nine traits significantly different across genotypes in males, but no differences were found in females. A substantial improvement in the regression of domains/traits score when gene–sex interactions were included further confirmed the dimorphism, e.g., the R-squared (adjusted) for the psychoticism improved from 0.03 (p = 0.15) to 0.19 (p < 0.001). Conclusions: Findings offer preliminary support for a link, potentially dimorphic across sexes, between the COMT Val158Met polymorphism and personality pathology as represented by the AMPD.

BackgroundNegative neuropsychiatric symptoms, such as apathy, are a core feature of Alzheimer’s disease. Previous studies have shown that levels of fasting plasma proline and differential activity of the catechol-O-methyltransferase (COMT) enzyme, which metabolises dopamine, influence negative symptoms in patients with severe psychiatric illness and those at risk for psychosis. For patients with the COMT high activity enzyme (as assessed via the COMT Val158Met polymorphism), high plasma proline was associated with less severe negative symptoms. Conversely, high proline was associated with more severe negative symptoms in patients with the low activity COMT enzyme.AimsIn this proof-of-concept cross-sectional study, we tested the hypothesis that proline and COMT Val158Met interact to modify negative symptom severity across neuropsychiatric disease, specifically now investigating patients with Alzheimer’s disease dementia.MethodLeast Absolute Shrinkage and Selection Operator regression was employed to model the interaction between proline and COMT on negative symptoms in n = 50 patients with probable Alzheimer’s disease or mild cognitive impairment with underlying Alzheimer’s disease biomarkers.ResultsThe proline × COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale, interaction coefficient 0.025, p = 0.031, with a trend toward significance when assessed via the Scale for Assessment of Negative Symptoms in Alzheimer’s disease, interaction coefficient 0.075, p = 0.055. Higher proline was beneficial for both Val/Val and Val/Met dementia patients, but detrimental to patients with the low activity Met/Met COMT enzyme.ConclusionsHigher proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia and further supports the development of therapeutics aimed at modulating this interaction pathway across neuropsychiatric disorders.

Genetic polymorphisms play a crucial role in regulating the physiological mechanisms underlying athletic performance, including muscle structure, energy metabolism, and cognitive functions. In recent years, increasing attention has been directed toward genetic variants that may influence cognitive traits such as motivation, stress tolerance, and attention, which are critical for optimal athletic performance. The present study aimed to provide the first preliminary meta-analysis of the association between athlete status and specific candidate polymorphisms related to cognitive processes (COMT rs4680, BDNF rs6265, OPRM1 rs1799971, and APOE rs7412/rs429358). A total of 17 case-control studies meeting the inclusion criteria were retrieved from relevant databases and included in the analysis. Statistical evaluations were performed using random- and fixed-effects models with a 95% confidence interval. The results indicated a potential association between the COMT Val158Met polymorphism and athlete status in both the overall and power athlete subgroups (p < 0.05). In contrast, no significant associations were observed for BDNF rs6265, OPRM1 rs1799971, or APOE rs7412/rs429358. However, this finding is based on a small number of studies and must be interpreted as exploratory. While this preliminary meta-analysis highlights a significant evidence gap, it also underscores, due to methodological limitations, the need for further empirical studies to understand the potential role of these polymorphisms in athlete status.

BackgroundEarlier age at menopause is a risk factor for cognitive decline and dementia. Carriers of the Met allele of the Val66Met polymorphism show decreased levels of brain‐derived neurotrophic factor (BDNF), which is associated with worse cognitive outcomes. Previous research suggests that higher BDNF levels may help mitigate the cognitive deficits associated with estrogen depletion in postmenopausal women. Physical activity (PA) increases BDNF levels and might further counteract the effects of earlier menopause and/or Met allele carriage on cognitive outcomes. Despite these known associations, the combined influence of these factors remains unknown. Here, we investigated whether BDNF genotype, age at menopause, and PA interact to influence cognition in postmenopausal women.MethodWe used baseline data from the Canadian Longitudinal Study on Aging. BDNF Val66Met genotype was dichotomized as Met carriers (Met/Met or Met/Val) vs. non‐carriers (Val/Val). Age at menopause was self‐reported. PA was measured using the Physical Activity Scale for the Elderly (PASE) score. Global cognition was assessed with neuropsychological tests and quantified with a composite of standardized scores. Linear regression models were used to test independent and interactive associations of age at menopause, Met carriage, and PASE score on cognitive scores, adjusting for age, years of education, and testing language (English/French).ResultsWe included N = 8,101 postmenopausal women (mean age=64.5±8.78 years, mean age at menopause=50.0±4.86 years, 33% Met carriers). In terms of independent effects, earlier menopause and lower PA were each associated with worse cognition (age at menopause: β = 0.070, p < .001; PA: β = 0.033, p = .001). However, Met carriage alone was not associated with cognition (β = 0.005, p = .81). Notably, there was a significant three‐way interaction between age at menopause, Met carriage, and PA on cognition. Specifically, greater PA levels attenuated the influence of earlier menopause on worse cognition in Met carriers, but not in non‐carriers (Figure 1; β = ‐0.048, p = .03). Sensitivity analysis adjusting for hormone therapy and vascular risk yielded similar results.ConclusionThese findings suggest that age at menopause, BDNF genotype, and PA synergistically influence cognition in postmenopausal women. Staying physically active may be particularly beneficial for cognitive health in women with the Met allele and an earlier age at menopause.

Background: Impulsivity is a multidimensional trait associated with the development and maintenance of behavioral and substance addictions. Genetic polymorphisms, particularly within the dopaminergic system, are thought to modulate individual differences in impulsivity. The COMT rs4680 (Val158Met) polymorphism influences enzymatic activity of catechol-O-methyltransferase and may alter dopaminergic tone in the prefrontal cortex. This study investigated whether COMT rs4680 genotype interacts with addiction status (behavioral and substance addictions) to influence trait impulsivity. Methods: The study included 309 Polish men: 128 with mixed behavioral and substance addictions and 181 healthy controls. All participants completed the Barratt Impulsiveness Scale (BIS-11) and were genotyped for COMT rs4680. A two-way ANOVA was used to assess main and interaction effects of genotype and group on total and subscale BIS-11 scores. Results: Individuals with mixed addictions scored significantly higher on all BIS-11 subscales (p < 0.01). A significant interaction effect was observed for the Non-Planning (F2,303 = 4.40, p = 0.0131, η2 = 0.028) and Total BIS-11 scale (F2,303 = 5.77, p = 0.0035, η2 = 0.037), with the A/A genotype associated with increased impulsivity, especially among the clinical group. Conclusions: These findings support a gene-by-environment interaction in impulsivity, where COMT rs4680 Met/Met homozygotes may be more susceptible to heightened impulsivity in addiction contexts. The results highlight the potential utility of COMT genotyping in personalizing therapeutic strategies for impulse-related disorders such as addictive disorders. This study extends evidence on dopaminergic modulation of impulsivity to behavioral and substance addictions.