Influence of BDNF Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases
Rodrigo Urbina-Varela1, María Inés Soto-Espinoza2, Romina Vargas1, Luis Quiñones3, Andrea del Campo1,*
1Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile. 2Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Chile. 3Laboratorio de Carcinogenesis Química y Farmacogenética (CQF), Departamento de Oncología Básico-Clínica, Facultad de Medicina, Universidad de Chile.
For the first time in history, most of the population has a life expectancy equal or greater than 60 years. By the year 2050, it is expected that the world population in that age range will reach 2000 million, an increase of 900 million with respect to 2015, which poses new challenges for health systems. In this way, it is relevant to analyze the most common diseases associated with the aging process, namely Alzheimer´s disease, Parkinson Disease and Type II Diabetes, some of which may have a common genetic component that can be detected before manifesting, in order to delay their progress. Genetic inheritance and epigenetics are factors that could be linked in the development of these pathologies. Some researchers indicate that the BDNF gene is a common factor of these diseases, and apparently some of its polymorphisms favor the progression of them. In this regard, alterations in the level of BDNF expression and secretion, due to polymorphisms, could be linked to the development and/or progression of neurodegenerative and metabolic disorders. In this review we will deepen on the different polymorphisms in the BDNF gene and their possible association with age-related pathologies, to open the possibilities of potential therapeutic targets.
Urbina-Varela Rodrigo,Soto-Espinoza María Inés,Vargas Romina, et al. Influence of BDNF Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases[J]. Aging and disease,
2020, 11(6): 1513-1526.
Figure 1. Intracellular and extracellular modifications of BDNF. Intracellular cleavage eliminates the pre-region sequence (green box), this modification results in the formation of the immature pro-neurotrophin isoform of BDNF (yellow+blue). Furin eliminates the pro domain sequence and generates the mature isoform of BDNF (blue). The intracellular division that leads to the formation of m-BDNF can also occur in the intracellular vesicles. The processing of BDNF is carried out by intracellular proteases, regulated convertases, and Furin. As a result, both isoforms pro-BDNF and m-BDNF are released into the extracellular space. In the extracellular route, the pro-BDNF released in the extracellular space is processed by metalloproteinases 2 and 9 (MMP2 and MMP9) and Plasmin. Pro-BDNF can act over Sortilin and p75NTR receptors, while the prodomain acts over Sortilin and m-BDNF exerts its functions through the activation of TrkB receptors.
Table 1 shows a list of the most relevant SNPs on the BDNF gene that have been correlated with diseases, mostly focus on those correlating with the aging process.
Major Depressive disorder Hypertension AD PD T2D Depression Asthma Allergic Rhinitis
PTSD Epilepsy 
Hippocampal Volume in cerebral injury 
Missense variant Thr2 Ile
Depression and suicide 
Depressive disorder Bipolar disorder 
Table 1 BDNF polymorphisms and their relationship with multiple diseases. Each polymorphism was looked up in SNPedia and verified in the reference.
Adachi N, Numakawa T, Richards M, Nakajima S, Kunugi H (2014). New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases. World J Biol Chem, 5:409-428.
Akatsu H, Yamagata HD, Kawamata J, Kamino K, Takeda M, Yamamoto T, et al. (2006). Variations in the BDNF gene in autopsy-confirmed Alzheimer’s disease and dementia with Lewy bodies in Japan. Dement Geriatr Cogn Disord, 22:216-222.
Aldoghachi AF, Tor YS, Redzun SZ, Lokman KAB, Razaq NAA, Shahbudin AF, et al. (2019). Screening of brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms and plasma BDNF levels among Malaysian major depressive disorder patients. PloS One, 14:e0211241.
Alharbi KK, Richardson TG, Khan IA, Syed R, Mohammed AK, Boustred CR, et al. (2014). Influence of adiposity-related genetic markers in a population of saudi arabians where other variables influencing obesity may be reduced. Dis Markers, 2014:758232.
Altmann V, Schumacher-Schuh AF, Rieck M, Callegari-Jacques SM, Rieder CRM, Hutz MH (2016). Val66Met BDNF polymorphism is associated with Parkinson’s disease cognitive impairment. Neurosci Lett, 615:88-91.
Andiappan AK, Parate PN, Anantharaman R, Suri BK, Wang DY, Chew FT (2011). Genetic variation in BDNF is associated with allergic asthma and allergic rhinitis in an ethnic Chinese population in Singapore. Cytokine, 56:218-223.
Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn J, et al. (1998). The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol, 140:911-923.
Basiak-Rasała A, Różańska D, Zatońska K (2019). Food groups in dietary prevention of type 2 diabetes. Rocz Panstw Zakl Hig, 70:347-357.
Bathina S, Das UN (2015). Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci AMS, 11:1164-1178.
Beard JR, Officer A, de Carvalho IA, Sadana R, Pot AM, Michel J-P, et al. (2016). The World report on ageing and health: a policy framework for healthy ageing. Lancet Lond Engl, 387:2145-2154.
Beckers S, Peeters A, Zegers D, Mertens I, Gaal LV, Van Hul W (2008). Association of the BDNF Val66Met variation with obesity in women. Mol Genet Metab, 95:110-112.
Blair LM, Pickler RH, Gugiu PC, Ford JL, Munro CL, Anderson CM (2020). Genetic Risk Factors for Poor Cognitive Development in Children With Low Birth Weight. Biol Res Nurs, 22:5-12.
Boots EA, Schultz SA, Clark LR, Racine AM, Darst BF, Koscik RL, et al. (2017). BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer’s Prevention. Neurology, 88:2098-2106.
Borroni B, Grassi M, Archetti S, Costanzi C, Bianchi M, Caimi L, et al. (2009). BDNF Genetic Variations Increase the Risk of Alzheimer’s Disease-Related Depression. J Alzheimers Dis, 18:867-875.
Bridi JC, Hirth F (2018). Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson’s Disease. Front Neurosci, 12:80.
Byrd AS, Toth AT, Stanford FC (2018). Racial Disparities in Obesity Treatment. Curr Obes Rep, 7:130-138.
Chuu JY-J, Taylor JL, Tinklenberg J, Noda A, Yesavage J, Murphy GM (2006). The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer’s disease. J Alzheimers Dis JAD, 9:43-49.
Combarros O, Infante J, Llorca J, Berciano J (2004). Polymorphism at codon 66 of the brain-derived neurotrophic factor gene is not associated with sporadic Alzheimer’s disease. Dement Geriatr Cogn Disord, 18:55-58.
Coskunoglu A, Orenay-Boyacioglu S, Deveci A, Bayam M, Onur E, Onan A, et al. (2017). Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus. Noise Health, 19:140-148.
da Costa RO, Gadelha-Filho CVJ, da Costa AEM, Feitosa ML, de Araújo DP, de Lucena JD, et al. (2017). The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats. Oxid Med Cell Longev, 2017:2138169.
Daily JW, Park S (2017). Interaction of BDNF rs6265 variants and energy and protein intake in the risk for glucose intolerance and type 2 diabetes in middle-aged adults. Nutr Burbank Los Angel Cty Calif, 33:187-194.
Diniz BS, Reynolds CF, Begley A, Dew MA, Anderson SJ, Lotrich F, et al. (2014). Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res, 49:96-101.
Diniz BS, Teixeira AL, Machado-Vieira R, Talib LL, Radanovic M, Gattaz WF, et al. (2014). Reduced cerebrospinal fluid levels of brain-derived neurotrophic factor is associated with cognitive impairment in late-life major depression. J Gerontol B Psychol Sci Soc Sci, 69:845-851.
Duman RS, Monteggia LM (2006). A neurotrophic model for stress-related mood disorders. Biol Psychiatry, 59:1116-1127.
Durmaz A, Kumral E, Durmaz B, Onay H, Aslan GI, Ozkinay F, et al. (2019). Genetic factors associated with the predisposition to late onset Alzheimer’s disease. Gene, 707:212-215.
Dwivedi Y (2013). Involvement of brain-derived neurotrophic factor in late-life depression. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry, 21:433-449.
Failla MD, Conley YP, Wagner AK (2016). Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury-Related Mortality: Interrelationships Between Genetics and Acute Systemic and Central Nervous System BDNF Profiles. Neurorehabil Neural Repair, 30:83-93.
Ferreira RN, de Miranda AS, Rocha NP, Simoes E Silva AC, Teixeira AL, da Silva Camargos ER (2018). Neurotrophic Factors in Parkinson’s Disease: What Have we Learned from Pre-Clinical and Clinical Studies? Curr Med Chem, 25:3682-3702.
Ferrer I, Marín C, Rey MJ, Ribalta T, Goutan E, Blanco R, et al. (1999). BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J Neuropathol Exp Neurol, 58:729-739.
Foltynie T, Lewis SGJ, Goldberg TE, Blackwell AD, Kolachana BS, Weinberger DR, et al. (2005). The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease. J Neurol, 252:833-838.
da Fonseca ACP, Abreu GM, Zembrzuski VM, Campos Junior M, Carneiro JRI, Nogueira Neto JF, et al. (2019). The association of the fat mass and obesity-associated gene (FTO) rs9939609 polymorphism and the severe obesity in a Brazilian population. Diabetes Metab Syndr Obes Targets Ther, 12:667-684.
Fonseca-Portilla R, Krell-Roesch J, Shaibi GQ, Caselli RJ, Mandarino LJ, Zhang N, et al. (2019). Brain-Derived Neurotrophic Factor and Its Associations with Metabolism and Physical Activity in a Latino Sample. Metab Syndr Relat Disord, 17:75-80.
Franzmeier N, Ren J, Damm A, Monté-Rubio G, Boada M, Ruiz A, et al. (2019). The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease. Mol Psychiatry. doi: 10.1038/s41380-019-0404-6.
Fu J, Li G, Li L, Yin J, Cheng H, Han L, et al. (2017). The role of established East Asian obesity-related loci on pediatric leptin levels highlights a neuronal influence on body weight regulation in Chinese children and adolescents: the BCAMS study. Oncotarget, 8:93593-93607.
Fu J, Wang Y, Li G, Han L, Li Y, Li L, et al. (2019). Childhood sleep duration modifies the polygenic risk for obesity in youth through leptin pathway: the Beijing Child and Adolescent Metabolic Syndrome cohort study. Int J Obes 2005, 43:1556-1567.
Fukumoto N, Fujii T, Combarros O, Kamboh MI, Tsai S-J, Matsushita S, et al. (2010). Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer’s disease: New data and meta-analysis. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet, 153B:235-242.
Giralt A, Friedman HC, Caneda-Ferrón B, Urbán N, Moreno E, Rubio N, et al. (2010). BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington’s disease. Gene Ther, 17:1294-1308.
Gökçe E, Güneş E, Nalçaci E (2019). Effect of Exercise on Major Depressive Disorder and Schizophrenia: A BDNF Focused Approach. Noro Psikiyatri Arsivi, 56:302-310.
Guerini FR, Beghi E, Riboldazzi G, Zangaglia R, Pianezzola C, Bono G, et al. (2009). BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol, 16:1240-1245.
Guo J-C, Yang Y-J, Guo M, Wang X-D, Juan Y, Gao Y-S, et al. (2018). Correlations of Four Genetic Single Nucleotide Polymorphisms in Brain-Derived Neurotrophic Factor with Posttraumatic Stress Disorder. Psychiatry Investig, 15:407-412.
Han X, Luo Y, Zhang X, Lv C, Sun X, Zhang X, et al. (2013). Rs4074134 near BDNF gene is associated with type 2 diabetes mellitus in Chinese Han population independently of body mass index. PloS One, 8:e56898.
Hao R, Qi Y, Hou D-N, Ji Y-Y, Zheng C-Y, Li C-Y, et al. (2017). BDNF val66met Polymorphism Impairs Hippocampal Long-Term Depression by Down-Regulation of 5-HT3 Receptors. Front Cell Neurosci, 11:306.
Hayes JP, Reagan A, Logue MW, Hayes SM, Sadeh N, Miller DR, et al. (2018). BDNF genotype is associated with hippocampal volume in mild traumatic brain injury. Genes Brain Behav, 17:107-117.
He X, Zhang Z, Zhang J, Zhou Y, Tang M, Wu C, et al. (2007). Lack of association between the BDNF gene Val66Met polymorphism and Alzheimer disease in a Chinese Han population. Neuropsychobiology, 55:151-155.
Hing B, Davidson S, Lear M, Breen G, Quinn J, McGuffin P, et al. (2012). A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity. Biol Psychiatry, 71:618-626.
Holmes SE, Esterlis I, Mazure CM, Lim YY, Ames D, Rainey-Smith S, et al. (2018). Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study. Int J Geriatr Psychiatry, 33:405-413.
Hotta K, Nakamura M, Nakamura T, Matsuo T, Nakata Y, Kamohara S, et al. (2009). Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. J Hum Genet, 54:727-731.
Hsiao Y-H, Chang C-H, Gean P-W (2018). Impact of social relationships on Alzheimer’s memory impairment: mechanistic studies. J Biomed Sci, 25:3.
Huang R, Huang J, Cathcart H, Smith S, Poduslo SE (2007). Genetic variants in brain-derived neurotrophic factor associated with Alzheimer’s disease. J Med Genet, 44:e66.
Ji H, Dai D, Wang Y, Jiang D, Zhou X, Lin P, et al. (2015). Association of BDNF and BCHE with Alzheimer’s disease: Meta-analysis based on 56 genetic case-control studies of 12,563 cases and 12,622 controls. Exp Ther Med, 9:1831-1840.
Jia W, Shi JG, Wu B, Ao L, Zhang R, Zhu YS (2011). Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence. Neurosci Lett, 495:221-224.
Karakasis C, Kalinderi K, Katsarou Z, Fidani L, Bostantjopoulou S (2011). Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with Parkinson’s disease in a Greek population. J Clin Neurosci Off J Neurosurg Soc Australas, 18:1744-1745.
Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J (2018). BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cell Mol Neurobiol, 38:579-593.
Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, et al. (2007). Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia, 50:431-438.
Lane CA, Hardy J, Schott JM (2018). Alzheimer’s disease. Eur J Neurol, 25:59-70.
Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A, et al. (2007). BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res, 41:387-394.
Lee YH, Song GG (2014). BDNF 196 G/A and 270 C/T polymorphisms and susceptibility to Parkinson’s disease: a meta-analysis. J Mot Behav, 46:59-66.
Licinio J, Dong C, Wong M-L (2009). Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry, 66:488-497.
Lim YY, Hassenstab J, Cruchaga C, Goate A, Fagan AM, Benzinger TLS, et al. (2016). BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease. Brain, 139:2766-2777.
Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, et al. (2014). Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer’s disease: a preliminary study. PloS One, 9:e86498.
Lin P-H, Tsai S-J, Huang C-W, Mu-En L, Hsu S-W, Lee C-C, et al. (2016). Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer’s disease. Oncotarget, 7:54200-54214.
Liu W, Han X, Zhou X, Zhang S, Cai X, Zhang L, et al. (2016). Brain derived neurotrophic factor in newly diagnosed diabetes and prediabetes. Mol Cell Endocrinol, 429:106-113.
Liu Q, Lei L, Yu T, Jiang T, Kang Y (2018). Effect of Brain-Derived Neurotrophic Factor on the Neurogenesis and Osteogenesis in Bone Engineering. Tissue Eng Part A, 24:1283-1292.
Liu Y-Q, Su G-B, Duan C-H, Wang J-H, Liu H-M, Feng N, et al. (2014). Brain-derived neurotrophic factor gene polymorphisms are associated with coronary artery disease-related depression and antidepressant response. Mol Med Rep, 10:3247-3253.
Lowell BB, Shulman GI (2005). Mitochondrial dysfunction and type 2 diabetes. Science, 307:384-387.
de Luis DA, Aller R, Izaola O, Primo D, Romero E (2017). rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor Is Associated with Diabetes Mellitus Type 2 in Caucasian Females with Obesity. Ann Nutr Metab, 70:286-292.
de Luis DA, Romero E, Izaola O, Primo D, Aller R (2017). Cardiovascular Risk Factors and Insulin Resistance after Two Hypocaloric Diets with Different Fat Distribution in Obese Subjects: Effect of the rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor. J Nutr Nutr, 10:163-171.
Martínez-García F, Mansego ML, Rojo-Martínez G, De Marco-Solar G, Morcillo S, Soriguer F, et al. (2013). Impact of obesity-related genes in Spanish population. BMC Genet, 14:111.
Matsushita S, Arai H, Matsui T, Yuzuriha T, Urakami K, Masaki T, et al. (2005). Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease. J Neural Transm Vienna Austria 1996, 112:703-711.
Miranda M, Morici JF, Zanoni MB, Bekinschtein P (2019). Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci, 13:363.
Mirkovic B, Laurent C, Podlipski M-A, Frebourg T, Cohen D, Gerardin P (2016). Genetic Association Studies of Suicidal Behavior: A Review of the Past 10?Years, Progress, Limitations, and Future Directions. Front Psychiatry, 7:158.
Oades RD, Lasky-Su J, Christiansen H, Faraone SV, Sonuga-Barke EJ, Banaschewski T, et al. (2008). The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav Brain Funct BBF, 4:48.
Pae C-U, Chiesa A, Porcelli S, Han C, Patkar AA, Lee S-J, et al. (2012). Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Neuropsychobiology, 65:1-11.
Parsian A, Sinha R, Racette B, Zhao JH, Perlmutter JS (2004). Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson’s disease. Parkinsonism Relat Disord, 10:213-219.
Peng S, Wuu J, Mufson EJ, Fahnestock M (2005). Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem, 93:1412-1421.
Phillips C (2017). Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection. Neural Plast, 2017:7260130.
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron, 7:695-702.
Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007). Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics, 90:397-406.
Razgado-Hernandez LF, Espadas-Alvarez AJ, Reyna-Velazquez P, Sierra-Sanchez A, Anaya-Martinez V, Jimenez-Estrada I, et al. (2015). The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson’s disease. PloS One, 10:e0117391.
Sadakata T, Furuichi T (2009). Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility. Cerebellum Lond Engl, 8:312-322.
Sasi M, Vignoli B, Canossa M, Blum R (2017). Neurobiology of local and intercellular BDNF signaling. Pflugers Arch, 469:593-610.
Sears C, Markie D, Olds R, Fitches A (2011). Evidence of associations between bipolar disorder and the brain-derived neurotrophic factor (BDNF) gene. Bipolar Disord, 13:630-637.
Shi J, Long J, Gao Y-T, Lu W, Cai Q, Wen W, et al. (2010). Evaluation of genetic susceptibility loci for obesity in Chinese women. Am J Epidemiol, 172:244-254.
Smith MA, Makino S, Kvetnansky R, Post RM (1995). Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci Off J Soc Neurosci, 15:1768-1777.
Sun RF, Zhu YS, Kuang WJ, Liu Y, Li SB (2011). The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia. Neurosci Lett, 489:34-37.
Suwa M, Kishimoto H, Nofuji Y, Nakano H, Sasaki H, Radak Z, et al. (2006). Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus. Metabolism, 55:852-857.
Szczepankiewicz A (2013). Evidence for single nucleotide polymorphisms and their association with bipolar disorder. Neuropsychiatr Dis Treat, 9:1573-1582.
Tonra JR, Ono M, Liu X, Garcia K, Jackson C, Yancopoulos GD, et al. (1999). Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice. Diabetes, 48:588-594.
Tysnes O-B, Storstein A (2017). Epidemiology of Parkinson’s disease. J Neural Transm Vienna Austria 1996, 124:901-905.
Varambally S, Naveen GH, Rao MG, Thirthalli J, Sharma R, Christopher R, et al. (2013). Low serum brain derived neurotrophic factor in non-suicidal out-patients with depression: Relation to depression scores. Indian J Psychiatry, 55:S397-399.
Ventriglia M, Bocchio Chiavetto L, Benussi L, Binetti G, Zanetti O, Riva MA, et al. (2002). Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer’s disease. Mol Psychiatry, 7:136-137.
Voisin S, Almén MS, Zheleznyakova GY, Lundberg L, Zarei S, Castillo S, et al. (2015). Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers. Genome Med, 7:103.
Voruganti VS (2018). Nutritional Genomics of Cardiovascular Disease. Curr Genet Med Rep, 6:98-106.
Wang Q, Liu J, Guo Y, Dong G, Zou W, Chen Z (2019). Association between BDNF G196A (Val66Met) polymorphism and cognitive impairment in patients with Parkinson’s disease: a meta-analysis. Braz J Med Biol Res Rev Bras Pesqui Medicas E Biol, 52:e8443.
Winick-Ng W, Rylett RJ (2018). Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer’s Disease. Front Mol Neurosci, 11:60.
Xiromerisiou G, Hadjigeorgiou GM, Eerola J, Fernandez HH, Tsimourtou V, Mandel R, et al. (2007). BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson’s disease in diverse ethnic groups. Neurosci Lett, 415:59-63.
Xu L, Tian D, Li J, Chen L, Tang L, Fan D (2017). The Analysis of Two BDNF Polymorphisms G196A/C270T in Chinese Sporadic Amyotrophic Lateral Sclerosis. Front Aging Neurosci, 9:135.
Yamanaka M, Itakura Y, Tsuchida A, Nakagawa T, Taiji M (2008). Brain-derived neurotrophic factor (BDNF) prevents the development of diabetes in prediabetic mice. Biomed Res Tokyo Jpn, 29:147-153.
Yang Y, Chen Y, Wu J, Xing Y, Zeng F, Huang Y, et al. (2014). [Association study of CNR1, GAD1 and BDNF polymorphisms with male heroin dependence in the Dai population in Yunnan]. Yi Chuan Hered, 36:888-896.
Yang J, Harte-Hargrove LC, Siao C-J, Marinic T, Clarke R, Ma Q, et al. (2014). proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep, 7:796-806.
Yinli C, Jie H, Li Z, Jun G, Peiling L, Weihong Y (2013). Association between brain-derived neurothropic factor variants and asthma in Chinese Han children. Acta Paediatr Oslo Nor 1992, 102:e247-250.
Youssef MM, Underwood MD, Huang Y-Y, Hsiung S-C, Liu Y, Simpson NR, et al. (2018). Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide. Int J Neuropsychopharmacol, 21:528-538.
Zeilinger S, Pinto LA, Nockher WA, Depner M, Klopp N, Illig T, et al. (2009). The effect of BDNF gene variants on asthma in German children. Allergy, 64:1790-1794.
Zhang XY, Chen D-C, Tan Y-L, Tan S-P, Luo X, Zuo L, et al. (2016). BDNF polymorphisms are associated with schizophrenia onset and positive symptoms. Schizophr Res, 170:41-47.
Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, et al. (2006). Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet, 141B:387-393.
Zhao J, Bradfield JP, Li M, Wang K, Zhang H, Kim CE, et al. (2009). The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI. Obes Silver Spring Md, 17:2254-2257.
Zhao M, Chen L, Yang J, Han D, Fang D, Qiu X, et al. (2018). BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction. J Affect Disord, 227:226-235.
Zhen Y-F, Liu X-Y, Zhou D-H, Du X, Yin G, Zhang Y, et al. (2018). Cognition, serum BDNF levels, and BDNF Val66Met polymorphism in type 2 diabetes patients and healthy controls. Oncotarget, 9:3653-3662.
Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, et al. (2013). Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology (Berl), 227:93-100.
Zhou J-X, Li H-C, Bai X-J, Chang B-C, Li C-J, Sun P, et al. (2013). Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects. Behav Brain Funct BBF, 9:34.
Zoladz JA, Majerczak J, Zeligowska E, Mencel J, Jaskolski A, Jaskolska A, et al. (2014). Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson’s disease patients. J Physiol Pharmacol Off J Pol Physiol Soc, 65:441-448.
Nir Barzilai, James C Appleby, Steven N Austad, Ana Maria Cuervo, Matt Kaeberlein, Christian Gonzalez-Billault, Stephanie Lederman, Ilia Stambler, Felipe Sierra. Geroscience in the Age of COVID-19[J]. Aging and disease, 2020, 11(4): 725-729.