Brain-derived Neurotrophic Factor Val66Met Polymorphism Research Articles

Association between the Val66Met (rs6265) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, BDNF protein level in the blood and the risk of developing early‑onset Parkinson's disease.

Brain-derived neurotrophic factor (BDNF) is involved in the maintenance of dopamine level and the survival of dopaminergic neurons, which may affect the functionality of brain structures responsible for motor and cognitive function. The aim of the study was to assess the association of individual and combined single nucleotide polymorphism (SNP) in the rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes with early‑onset of Parkinson's disease (PD) patients. Moreover, we assessed the association between the BDNF Val66Met polymorphism and the level of BDNF protein in the serum of patients with PD and controls. The study involved 163 patients with idiopathic PD divided into early onset (<55 years) and late‑onset (>55 years) groups and 91 healthy age‑matched people (Control). The SNP were determined using the TaqMan Real‑Time PCR method. Serum BDNF levels were determined by ELISA assay. The risk of developing early PD in people with the BDNF genotype AG increases threefold in comparison with the carriers of the BDNF genotype GG. In PD patients and healthy people with the BDNF genotypes AG and AA, a lower serum BDNF level was found compared to those with the BDNF genotype GG in both groups. The results of our study indicate that the presence of the Val66Met BDNF gene polymorphism is associated with reduced blood BDNF levels and an elevated risk of developing early‑onset PD. This effect appears to be more pronounced in men.

Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Sex Differences in the Effect of Brain-derived Neurotrophic Factor (BDNF) Val66Met Polymorphism on Baseline EEG Connectivity

Dependent on Val66Met polymorphism in BDNF gene secretion of neurotrophin affects morphological and functional changes in the developing and mature nervous system, in particular, may contribute to associated with white matter degradation changes in connectivity observed with aging. It was also shown that the associated with Val66Met polymorphism differences in connectivity between cortical structures are moderated by the sex of the subjects. However, there are no studies examining the effect of polymorphism on connectivity, taking into account age and gender differences. In this regard, the present study examined the associations of the Val66Met polymorphism of the BDNF gene with the characteristics of delayed phase synchronization based on EEG data in 223 younger (from 18 to 35 years old) and 134 older (over 55 years old) men and women. The analysis included connections between 84 cortical areas, identified on the basis of 42 Brodmann areas located in the left and right hemispheres. A statistically significant effect, including the factor of polymorphism, was the SEX × GENOTYPE interaction when considering associations at the frequency of the α1-rhythm: in Val/Met men, the strength of thirty-three connections was higher compared to Val/Val. Strengthening of connections was observed mainly between the parahippocampal regions of different hemispheres. At the frequency of the gamma rhythm, associated with the genotype differences in connectivity depended on gender and age. In young subjects, the scores of connectivity in Val/Val women were lower in comparison with men, however, no differences between Val/Val and Met carriers were found in any age group. The combined effect of sex and BDNF genotype on the baseline EEG parameters of brain connectivity may be a background for further study of the role of these factors in the formation of basic characteristics of brain activity.

Genetic polymorphisms and post-stroke upper limb motor improvement - A systematic review and meta-analysis.

Post-stroke upper limb (UL) motor improvement is associated with adaptive neuroplasticity and motor learning. Both intervention-related (including provision of intensive, variable, and task-specific practice) and individual-specific factors (including the presence of genetic polymorphisms) influence improvement. In individuals with stroke, most commonly, polymorphisms are found in Brain Derived Neurotrophic Factor (BDNF), Apolipoprotein (APOE) and Catechol-O-Methyltransferase (COMT). These involve a replacement of cystine by arginine (APOEε4) or valines by 1 or 2 methionines (BDNF:val66met, met66met; COMT:val158met; met158met). However, the implications of these polymorphisms on post-stroke UL motor improvement specifically have not yet been elucidated. Examine the influence of genetic polymorphism on post-stroke UL motor improvement. Systematic Review and Meta-Analysis. We conducted a systematic search of the literature published in English language. The modified Downs and Black checklist helped assess study quality. We compared change in UL motor impairment and activity scores between individuals with and without the polymorphisms. Meta-analyses helped assess change in motor impairment (Fugl Meyer Assessment) scores based upon a minimum of 2 studies/time point. Effect sizes (ES) were quantified based upon the Rehabilitation Treatment Specification System as follows: small (0.08-0.18), medium (0.19 -0.40) and large (≥0.41). We retrieved 10 (4 good and 6 fair quality) studies. Compared to those with BDNF val66met and met66met polymorphism, meta-analyses revealed lower motor impairment (large ES) in those without the polymorphism at intervention completion (0.5, 95% CI: 0.11-0.88) and at retention (0.58, 95% CI:0.06-1.11). The presence of CoMT val158met or met158met polymorphism had similar results, with lower impairment (large ES ≥1.5) and higher activity scores (large ES ranging from 0.5-0.76) in those without the polymorphism. Presence of APOEε4 form did not influence UL motor improvement. Polymorphisms with the presence of 1 or 2 met alleles in BDNF and COMT negatively influence UL motor improvement. https://osf.io/wk9cf/.

Association between reduced plasma BDNF concentration and MMSE scores in both chronic schizophrenia and mild cognitive impairment

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.

Association between Brain-derived Neurotrophic Factor (BDNF) Val66Met polymorphism and Clinical Outcomes as Measured with PANSS Scale in Patients With Schizophrenia in Two Psychiatric Centres in East Java – Indonesia

Aim: The etiology of schizophrenia has been linked to complex interactions of genetic and environmental factors, and among them are genes that regulate BDNF (Brain-derived Neurotrophic Factor) expression. The BDNF has been linked to the pathophysiology of schizophrenia, particularly the Val66Met polymorphism. This study aims to assess BDNF Val66Met polymorphism and its role in positive and negative symptoms in patients with schizophrenia in East Java. Subjects and Methods: A total of 52 subjects with schizophrenia living in East Java were assessed for BDNF Val66Met polymorphism. The analysis was performed using Statistical the Social Sciences (SPSS) software version 22. Clinical assessment was conducted using the positive and negative syndrome scale (PANSS). Data were analyzed using linear regression multivariate analysis. Results: Our study found that Val/Met polymorphism is associated negatively with the total PANSS scores (beta coefficient = -12.299, p = 0.017). The Val/Val polymorphism is associated with negative symptoms (beta coefficient = 22.607, p = 0.043). The present study’s findings considered age, gender, education level, number of antipsychotics consumed, medication adherence, and duration of untreated psychosis. Conclusion: Val/Val polymorphism is associated with a higher PANSS total score. Val/Met genotype is associated with more severe positive symptoms, while the Val/Val genotype is associated with more negative symptoms. Further study with a larger and multicenter sample is needed to clarify further the relationship of BDNF polymorphism to clinical outcomes of schizophrenia.

The BDNF Val66Met polymorphism and health-related quality of life in youth with obesity.

The brain derived-neurotrophic factor (BDNF) Val66Met polymorphism causes functional changes in BDNF, and is associated with obesity and some psychiatric disorders, but its relationship to health-related quality of life (HRQoL) remains unknown. This study examined, in youth with obesity, whether carriers of the BDNF Val66met polymorphism Met-alleles (A/A or G/A) differed from noncarriers (G/G) on HRQoL. The participants were 187 adolescents with obesity. Ninety-nine youth were carriers of the homozygous Val/Val (G/G) alleles, and 88 were carriers of the Val/Met (G/A) or Met/Met (A/A) alleles. Blood samples were drawn in the morning after an overnight fast for genotyping. HRQoL was measured using the Pediatric-Quality of Life core version. Compared to carriers of the Val66Met Val (G/G) alleles, carriers of the Met-Alleles reported significantly higher physical -HRQoL (p = 0.02), school-related HRQoL, (p = 0.05), social-related HRQoL (p = 0.05), and total HRQoL (p = 0.03), and a trend for Psychosocial-HRQoL. Research is needed to confirm our findings and determine whether carriers of the BDNF Val66Met homozygous Val (G/G) alleles may be at risk of diminished HRQoL, information that can influence interventions in a high-risk population of inactive youth with obesity.

A pilot study of the role of the BDNF Val66Met polymorphism in response to exercise-augmented exposure therapy for posttraumatic stress disorder

Brain-Derived Neurotrophic Factor (BDNF) is implicated in extinction learning, which is a primary mechanism of exposure therapy for posttraumatic stress disorder (PTSD). Brief aerobic exercise has been shown to promote BDNF release and augment extinction learning. On the premise that the Val allele of the BDNF Val66Met polymorphism facilitates greater release of BDNF, this study examined the extent to which the Val allele of the BDNF polymorphism predicted treatment response in PTSD patients who underwent exposure therapy combined with aerobic exercise or passive stretching. PTSD patients (N = 85) provided saliva samples in order to extract genomic DNA to identify Val/Val and Met carriers of the BDNF Val66Met genotype, and were assessed for PTSD severity prior to and following a 9-week course of exposure therapy combined with aerobic exercise or stretching. The sample comprised 52 Val/Val carriers and 33 Met carriers. Patients with the BDNF high-expression Val allele display greater reduction of PTSD symptoms at posttreatment than Met carriers. Hierarchical regression analysis indicated that greater PTSD reduction was specifically observed in Val/Val carriers who received exposure therapy in combination with the aerobic exercise. This finding accords with animal and human evidence that the BDNF Val allele promotes greater extinction learning, and that these individuals may benefit more from exercise-augmented extinction. Although preliminary, this result represents a possible avenue for augmented exposure therapy in patients with the BDNF Val allele.

Cyberbullying victimization and psychopathological symptoms among adolescents varied in BDNF Val66Met polymorphism and vagal tone

BackgroundCyberbullying victimization increases psychopathological symptoms among adolescents. Brain-derived neurotrophic factor (BDNF) gene rs6265 polymorphism or vagal tone as individual diathesis or plasticity has been identified to interact with adverse experiences to affect developmental psychopathology. However, how these different individual factors combined to interact with adverse experiences to affect developmental psychopathology remains unknown. This study sought to investigate the integrally moderating role of BDNF gene rs6265 polymorphism and vagal tone in the relationship between cyberbullying victimization and psychopathological symptoms among adolescents. MethodsThe Cyberbullying Victimization Scale (CVS) and the Youth Self-Report (YSR-2001-CV) were administered to 382 junior school students, their saliva were collected for DNA genotyping and 5 min resting high frequency heart rate variability (HF-HRV) were recorded for assessing vagal tone. ResultsA positive relation between cyberbullying victimization and psychopathological symptoms was found, and this relation was independently and jointly moderated by resting HF-HRV and BDNF gene rs6265 polymorphism. Specifically, the relation was weaker only among adolescents with Val/Val genotype and low resting HF-HRV, but not those with Val/Val genotype and high resting HF-HRV, or Met/Met or Val/Met genotype regardless of resting HF-HRV. ConclusionThese findings suggest a combined moderating effect of BDNF gene rs6265 polymorphism and vagal tone on the relation between cyberbullying victimization and psychopathological symptoms among adolescents.

Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.

Sex Differences in the Effect of Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism on Baseline EEG Connectivity

Sex Differences in the Effect of Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism on Baseline EEG Connectivity

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Potential role of APOE ɛ4 allele as a modifier for the association of BDNF Val66Met polymorphisms and cognitive impairment in community-dwelling older adults.

To determine whether the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with cognitive impairment (CI) in community-dwelling Chinese older adults, and to investigate whether this relationship is modified by the Apolipoprotein E (APOE) ɛ4 allele. The study is a secondary analysis of 703 participants aged ≥60 years randomly enrolled from the Beijing Longitudinal Study of Aging II prospective cohort. The education-adjusted Mini-Mental State Examination and the Clinical Dementia Rating Scale were used to measure the cognitive performance of the subjects. The main effects and interactions (additive and multiplicative) of the BDNF Met and the APOE ε4 alleles on CI were estimated by logistic regression models. In total, 84 out of 703 older adults aged ≥60 years old had CI. No significant difference was observed in the risk of CI between participants with the BDNF Met allele and that of subjects without the BDNF Met allele (p = 0.213; p = 0.164). Individuals carrying both the BDNF Met and APOE ε4 alleles had an almost 1.5-fold increased odds of CI compared with carriers of the BDNF Met allele but without the APOE ε4 allele. The additive association indicated a positive interaction of both BDNF Met and APOE ε4 alleles with wide CIs (p = 0.021; p = 0.018). The results suggest that the APOE ε4 allele may be a potential modifier for the association of the BDNF Val66Met polymorphism with CI in community-dwelling older adults.

Brain-derived Neurotrophic Factor Level and Gene Polymorphism as Risk Factors for Depression in Patients with type 2 Diabetes Mellitus- A Case-Controlled Study.

Diabetes mellitus and depression are comorbidities that can be caused by each other. Brain-derived neurotrophic factor (BDNF) functions as a neuronal growth factor. It maintains the functional integrity of the nervous system. To study the possible association between BDNF levels and gene polymorphism with depression in patients diagnosed with type 2 diabetes mellitus. The Elisa technique measured BDNF, and rs6265 gene polymorphism was detected using real-time PCR. Depression was assessed utilizing a clinical interview tool designed to establish the diagnosis of depression and differentiate it from other psychiatric diseases. BDNF levels were significantly lower in patients with type 2 diabetes mellitus and symptoms of depression than in patients with type 2 diabetes mellitus and no symptoms of depression (82.6±16.1. Vs 122± 17.47, p˂ 0.001). There was a statistically significant difference in BDNF levels in patients with diabetes among the three genotypes of the BDNF gene (p-value < 0.001). Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. Subgroup analysis showed statistically significant genotype-related differences in serum BDNF levels among the three subgroups in the Depression group. Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. BDNF Val66Met polymorphism had no significant association with the presence of depression, yet there was a trend towards significance (p = 0.05) Conclusion: In this pilot, Low levels of BDNF were associated with depression in patients with type 2 diabetes. Carriers of the Met/ Met allele have the lowest serum BDNF levels. Multicenter studies with more participants are required.

The BDNF Val66Met polymorphism serves as a potential marker of body weight in patients with psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) is a predominant neurotrophic factor in the brain, indispensable for neuronal growth, synaptic development, neuronal repair, and hippocampal neuroplasticity. Among its genetic variants, the BDNF Val66Met polymorphism is widespread in the population and has been associated with the onset and aggravation of diverse pathologies, including metabolic conditions like obesity and diabetes, cardiovascular ailments, cancer, and an array of psychiatric disorders. Psychiatric disorders constitute a broad category of mental health issues that influence mood, cognition, and behavior. Despite advances in research and treatment, challenges persist that hinder our understanding and effective intervention of these multifaceted conditions. Achieving and maintaining stable body weight is pivotal for overall health and well-being, and the relationship between psychiatric conditions and body weight is notably intricate and reciprocal. Both weight gain and loss have been linked to varying mental health challenges, making the disentanglement of this relationship critical for crafting holistic treatment strategies. The BDNF Val66Met polymorphism's connection to weight fluctuation in psychiatric patients has garnered attention. This review investigated the effects and underlying mechanisms by which the BDNF Val66Met polymorphism moderates body weight among individuals with psychiatric disorders. It posits the polymorphism as a potential biomarker, offering prospects for improved monitoring and therapeutic approaches for mental illnesses.

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators

Background/Objective(1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. MethodThis study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. ResultsThe exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. ConclusionsAPOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.

Brain-Derived Neurotrophic Factor Val66Met is Associated with Variation in Cortical Structure in Healthy Aging Subjects.

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.

Day‐to‐day Sleep Variability in Val66Met BDNF Carriers: A Potential Biological Pathway Between BDNF Activity and Alzheimer’s Disease Pathology?

AbstractBackgroundWe previously showed that day‐to‐day sleep variability was associated with biomarkers of Alzheimer’s disease (AD) pathology. Given that brain‐derived neurotrophic factor (BDNF) activity has been involved in both AD and cognitive impacts of lifestyle risk factors, we sought to evaluate day‐to‐day sleep variability in those carrying the Met allele of the Val66Met BDNF polymorphism, which affects BDNF release. Additionally, we explored whether BDNF polymorphism modified the association between CSF AD pathology and day‐to‐day sleep variability.MethodThe PREVENT‐AD cohort enrolls dementia‐free persons with a parental history of sporadic AD. We characterized 203 dementia‐free participants from this cohort at the polymorphic BDNF locus, identifying 136 persons with genotype Val/Val (age 68.2±5.3y, 75%women), 67 Met heterozygotes/homozygotes (68.4±5.6y, 73% women, including six Met/Met homozygotes). After a week of actigraphy, we calculated these participants’ standard deviation of day‐to‐day sleep characteristics. We used t‐tests to compare day‐to‐day sleep variability in sleep characteristics between Val homozygotes and Met carriers. In a subsample of 101 participants, we assayed CSF Aβ42, t‐tau and p‐tau181, and used age‐ and sex‐adjusted linear regressions with an interaction term to test for moderation by BDNF genotype (36 Met carriers vs. 65 Val homozygotes) between sleep variability and CSF biomarker results.ResultAs compared to Val homozygotes, sleep was disturbed and unstable in BDNF Met carriers (heterozygotes/homozygotes). They had higher day‐to‐day variability in sleep fragmentation (activity counts, wake after sleep onset, fragmentation index), sleep onset latency, and sleep duration, resulting in weekly sleep patterns that were more fragmented and less efficient. Further, BDNF genotype moderated the association between CSF t‐tau and p‐tau181 with day‐to‐day sleep duration variability, such that only Met carriers showed an association between elevated tau concentration and sleep duration variability.ConclusionBDNF Met carriers had disturbed and unstable daily sleep patterns. Because the Met allele is known to decrease plasticity of neural mechanisms, the ability to achieve healthy and stable sleep may depend on such mechanisms. Thus, poorer sleep in Met carriers might be a biological mechanism by which altered BDNF activity affects tau pathology or, alternatively, accumulated AD pathology in Met carriers may disrupt sleep‐wake patterns.

54 The Differential Impact of Genetic Moderators on the Relationship Between Depression and Cognition

Objective:Depression has a well-established negative effect on cognitive functioning. Variations in the apolipoprotein e (APOE) and brain-derived neurotrophic factor (BDNF) genes likely contribute to this relationship. APOE4 and the BDNF Val66Met polymorphism are independently associated with late-life depression and cognitive dysfunction. The current study investigated the moderating effects of APOE4 and BDNFMet (i.e., the presence of the BDNF Val66Met polymorphism) on the relationship between depression and cognitive functioning in older adults.Participants and Methods:The sample included 103 older adults drawn from two clinical trials who were recruited from the VA Palo Alto Health Care System (VAPAHCS) and the Stanford/VA Alzheimer’s Disease Center. Depression was diagnosed using the Mini Neuropsychiatric Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). The presence of an APOE4 and BDNFMet allele were dichotomized (i.e., yes/no) and determined using venipuncture. A comprehensive neuropsychological battery was used to assess attention (RAVLT Trial 1, WAIS-IV DSF), processing speed (TMTA, SDMT, Stroop Word, Stroop Color), working memory (WAIS-IV DSB, DSS), visuospatial functioning (JLO), language (VNT), memory (RAVLT Delayed Recall, WMS-IV Logical Memory II), and executive function (TMTB, Stroop Color-Word). Separate moderation analyses were conducted with depression as the predictor and APOE4 or BDNFMet status as the moderator using the SPSS PROCESS macro v4.0. Age was a covariate for models with processing speed, memory, language, and executive function as outcome variables.Results:Participants were largely male (93%) and White (75%). Ten percent met criteria for depression, 26% were APOE4 carriers, and 32% were BDNFMet carriers. The overall model examining depression, APOE4, and memory was significant (p &lt; .01, R2 = .14). Depression was associated with lower memory performance (p &lt; .05), however, APOE4 was not a significant moderator (p &gt; .05). Similarly, the overall model examining depression, APOE4, and language was also significant (p &lt; .05, R2 = .10). While the direct effects of depression and APOE4 on language were nonsignificant (p &gt; .05), there was a significant two-way interaction between APOE4 and depression (p = .03). The overall model with depression, BDNFMet, and memory was significant (p &lt; .001, R2 = .18). While neither depression nor BDNFMet had significant direct effects on memory (p &gt; .05), a two-way interaction emerged between depression and BDNFMet (p = .05). Simple slopes analyses were used to further investigate significant interactions. Depression, APOE4, and BDNFMet did not significantly impact attention, processing speed, working memory, visuospatial functioning, or executive function, and no significant interactions were noted among variables. BDNFMet had no direct impact on language.Conclusions:APOE4 and BDNFMet were found to differentially moderate the relationship between depression and cognition. Specifically, APOE4 carriers with depression had worse language performance compared to those who were healthy, depressed, or APOE4 carriers. BDNFMet carriers with depression performed worse on measures of memory compared to those who were healthy, depressed, or BDNFMet carriers. The treatment of depression in APOE4 and BDNFMet carriers may reduce associated cognitive impairments. Limitations and future implications are also discussed.

Influence of BDNF Val66Met genetic polymorphism in Major Depressive Disorder and Body Mass Index: Evidence from a meta-analysis of 6481 individuals

BackgroundMajor depressive disorder (MDD) and obesity are global health problems that frequently co-occur. Among shared etiological factors, genetic variation at the brain-derived neurotrophic factor (BDNF) gene is interesting since its implication in energy balance regulation, food intake and synaptic function. Thus, the aim of this study was to investigate the influence of the BDNF Val66Met polymorphism in relation to MDD and body mass index (BMI) in two large independent cohorts. MethodsThe sample consisted of 2646 individuals with MDD and 3835 controls from the PISMA-ep and Radiant studies. Linear regressions were performed to test the association between the polymorphism and BMI and the interaction between the polymorphism and MDD on BMI. A meta-analysis across cohorts was conducted. ResultsNo association was found between the polymorphism and BMI. However, we found an association with MDD, showing these individuals higher BMI than controls in both cohorts. No differences were found in BMI depending on Val66Met genotype and no interaction between this polymorphism and MDD in relation to BMI was found. Although a tendency towards an interaction was found in the Radiant sample, the results of the meta-analysis did not support this finding. LimitationsThe use of self-reported height and weight measures to calculate BMI values. ConclusionsWe provide evidence for an association between BMI and MDD confirming previous results. Our meta-analysis including two large cohorts showed no interaction between BDNF, BMI and MDD. Future studies will be needed to confirm the role of this polymorphism in the relationship between BMI and MDD.