, Volume 34, Issue 4, pp 1011–1022 | Cite as

Brain-derived neurotrophic factor (BDNF) gene: a gender-specific role in cognitive function during normal cognitive aging of the MEMO-Study?

  • Katharine R. Laing
  • David Mitchell
  • Heike Wersching
  • Maria E. Czira
  • Klaus Berger
  • Bernhard T. BauneEmail author


Cognitive aging processes are underpinned by multiple processes including genetic factors. The brain-derived neurotrophic factor (BDNF) has been suggested to be involved in age-related cognitive decline in otherwise healthy individuals. The gender-specific role of the BDNF gene in cognitive aging remains unclear. The identification of genetic biomarkers might be a useful approach to identify individuals at risk of cognitive decline during healthy aging processes. The aim of this study was to investigate the associations between three single-nucleotide polymorphisms (SNPs) in the BDNF gene and domains of cognitive functioning in normal cognitive aging. The sample, comprising 369 participants (M = 72.7 years, SD = 4.45 years), completed an extensive neuropsychological test battery measuring memory, motor function, and perceptual speed. The relationships between the SNPs rs6265, rs7103411, and rs7124442 and cognitive domains were examined. While significant main effects of BDNF SNPs on cognitive function were found for the association between rs7103411 and memory performance, gender-specific analyses revealed for females significant main effects of rs7103411 for memory and of rs6265 for perceptual speed independent of the APOE*E4 status and education. The finding for the association between rs6265 and perceptual speed in females remained significant after Bonferroni correction for multiple comparisons. None of the analyses showed significant results for males. This study is the first to implicate that the SNPs rs6265 and rs7103411 affect cognitive function in the elderly in a gender-specific way.


BDNF BDNF gene Memory Motor function Perceptual speed Elderly Gender 



The MEMO-Study is supported by the German Research Society (Deutsch Forschungsgemeinschaft, Grant: BE1996/1-1). Data assessment was done within the framework of the Cooperative Health Research in the Augsburg Region (KORA). Bernhard Baune had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


  1. Baune BT, Suslow T, Engelien A, Arolt V, Berger K (2006) The association between depressive mood and cognitive performance in an elderly general population - the MEMO Study. Dement Geriatr Cogn Disord 22(2):142–149PubMedCrossRefGoogle Scholar
  2. Baune B, Ponath G, Rothermundt M, Riess O, Funke H, Berger K (2008) Association between genetic variants of IL-1 [beta], IL-6 and TNF-[alpha] cytokines and cognitive performance in the elderly general population of the MEMO-Study. Psychoneuroendocrinology 33:68–76PubMedCrossRefGoogle Scholar
  3. Beckman L, Nilsson L (1996) Semantic memory functioning across the adult life span. Eur Psychol 1:27–33CrossRefGoogle Scholar
  4. Cheng S, Grow M, Pallaud C, Klitz W, Erlich H, Visvikis S, Chen J, Pullinger C, Malloy M, Siest G (1999) A multilocus genotyping assay for candidate markers of cardiovascular disease risk. Genome Res 9:936PubMedCrossRefGoogle Scholar
  5. Chiang MC, Barysheva M, Toga AW, Medland SE, Hansell NK, James MR, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, Thompson PM (2011) BDNF gene effects on brain circuitry replicated in 455 twins. NeuroImage 55:448–454PubMedCrossRefGoogle Scholar
  6. Costa L, Vaughan H Jr, Levita E, Farber N (1963) Purdue Pegboard as a predictor of the presence and laterality of cerebral lesions. J Consult Psychol 27:133–137PubMedCrossRefGoogle Scholar
  7. Desrosiers J, Hebert R, Bravo G, Dutil E (1995) The Purdue Pegboard Test: normative data for people aged 60 and over. Disabil Rehabil 17:217–224PubMedCrossRefGoogle Scholar
  8. Egan M, Kojima M, Callicott J, Goldberg T, Kolachana B, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRefGoogle Scholar
  9. Ferrer I, Marin C, Rey M, Ribalta T, Goutan E, Blanco R, Tolosa E, Marti E (1999) BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J Neuropathol Exp Neurol 58:729PubMedCrossRefGoogle Scholar
  10. Foltynie T, Lewis S, Goldberg T, Blackwell A, Kolachana B, Weinberger D, Robbins T, Barker R (2005) The BDNF Val 66 Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease. J Neurol 252:833–838PubMedCrossRefGoogle Scholar
  11. Foltynie T, Cheeran B, Williams-Gray C, Edwards M, Schneider S, Weinberger D, Rothwell J, Barker R, Bhatia K (2009) BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson′s disease. J Neurol Neurosurg Psychiatry 80:141PubMedCrossRefGoogle Scholar
  12. Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonca VA, Izzo G, Gattaz WF (2010) Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry 11:774–780PubMedCrossRefGoogle Scholar
  13. Guerini FR, Beghi E, Riboldazzi G, Zangaglia R, Pianezzola C, Bono G, Casali C, Di Lorenzo C, Agliardi C, Nappi G, Clerici M, Martignoni E (2009) BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol 16:1240–1245PubMedCrossRefGoogle Scholar
  14. Hariri A, Goldberg T, Mattay V, Kolachana B, Callicott J, Egan M, Weinberger D (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690PubMedGoogle Scholar
  15. Harris S, Fox H, Wright A, Hayward C, Starr J, Whalley L, Deary I (2006) The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills. Mol Psychiatry 11:505–513PubMedCrossRefGoogle Scholar
  16. Hayashi M, Yamashita A, Shimizu K (1997) Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging. Brain Res 749:283–289PubMedCrossRefGoogle Scholar
  17. Hayashi M, Mistunaga F, Ohira K, Shimizu K (2001) Changes in BDNF-immunoreactive structures in the hippocampal formation of the aged macaque monkey. Brain Res 918:191–196PubMedCrossRefGoogle Scholar
  18. Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57:846PubMedCrossRefGoogle Scholar
  19. Howells D, Porritt M, Wong J, Batchelor P, Kalnins R, Hughes A, Donnan G (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166:127–135PubMedCrossRefGoogle Scholar
  20. 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:e66PubMedCrossRefGoogle Scholar
  21. Jones K, Reichardt L (1990) Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci 87:8060PubMedCrossRefGoogle Scholar
  22. Keil U, Liese A, Hense H, Filipiak B, Doring A, Stieber J, Lowel H (1998) Classical risk factors and their impact on incident non-fatal and fatal myocardial infarction and all-cause mortality in southern Germany: results from the MONICA Augsburg Cohort Study 1984–1992. Eur Heart J 19:1197PubMedCrossRefGoogle Scholar
  23. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka T, Kivipelto M, Hassinen M, Rauramaa T, Pedersen B, Rauramaa R (2008) BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA Study. Neurobiol Learn Mem 90:596–603PubMedCrossRefGoogle Scholar
  24. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci 92:8856PubMedCrossRefGoogle Scholar
  25. Korte M, Griesbeck O, Gravel C, Carroll P, Staiger V, Thoenen H, Bonhoeffer T (1996) Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci USA 93:12547PubMedCrossRefGoogle Scholar
  26. Korte M, Kang H, Bonhoeffer T, Schuman E (1998) A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology 37:553–559PubMedCrossRefGoogle Scholar
  27. Linnarsson S, Bjorklund A, Ernfors P (1997) Learning deficit in BDNF mutant mice. Eur J Neurosci 9:2581–2587PubMedCrossRefGoogle Scholar
  28. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136PubMedCrossRefGoogle Scholar
  29. Mattson M, Maudsley S, Martin B (2004) A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res Rev 3:445–464PubMedCrossRefGoogle Scholar
  30. Mercader J, Ribasés M, Gratacòs M, González J, Bayés M, de Cid R, Badía A, Fernández-Aranda F, Estivill X (2007) Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav 6:706–716PubMedCrossRefGoogle Scholar
  31. Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A (2008) Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7:411–417PubMedCrossRefGoogle Scholar
  32. Morris R (1989) Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-d-aspartate receptor antagonist AP5. J Neurosci 9:3040PubMedGoogle Scholar
  33. Narisawa-Saito M, Wakabayashi K, Tsuji S, Takahashi H, Nawa H (1996) Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer’s disease. Neuroreport 7:2925PubMedCrossRefGoogle Scholar
  34. Nilsson L, Söderlund H, Berger K, Breteler M, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Hofman A, Pajak A (2005) Cognitive test battery of CASCADE: tasks and data. Aging Neuropsychol Cogn 12:32–56CrossRefGoogle Scholar
  35. Nyberg L, Maitland S, Ronnlund M, Backman L, Dixon R, Wahhn A, Nilsson L (2003) Selective adult age differences in an age-invariant multifactor model of declarative memory. Psychol Aging 18:149–160PubMedCrossRefGoogle Scholar
  36. Oeth P, Beaulieu M, Park C, Kosman D, del Mistro G, van den Boom D, Jurinke C (2007) iPLEX™ assay: increased plexing efficiency and flexibility for MassARRAY system through single base primer extension with mass-modified terminators. Online access:
  37. Oroszi G, Lapteva L, Davis E, Yarboro C, Weickert T, Roebuck-Spencer T, Bleiberg J, Rosenstein D, Pao M, Lipsky P (2006) The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis 65:1330PubMedCrossRefGoogle Scholar
  38. Parain K, Murer M, Yan Q, Faucheux B, Agid Y, Hirsch E, Raisman-Vozari R (1999) Reduced expression of brain-derived neurotrophic factor protein in Parkinson’s disease substantia nigra. Neuroreport 10:557PubMedCrossRefGoogle Scholar
  39. Perneger TV (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238PubMedCrossRefGoogle Scholar
  40. Phillips H, Hains J, Armanini M, Laramee G, Johnson S, Winslow J (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7:695–702PubMedCrossRefGoogle Scholar
  41. Raz N, Rodrigue K, Kennedy K, Land S (2009) Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE and hypertension. Neuropsychology 23:105PubMedCrossRefGoogle Scholar
  42. Rybakowski JK, Borkowska A, Czerski PM, Skibiska M, Hauser J (2003) Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord 5:468–472PubMedCrossRefGoogle Scholar
  43. Rybakowski J, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P, Leszczynska-Rodziewicz A, Czerski P, Hauser J (2006) Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. Psychiatry Clin Neurosci 60:70–76PubMedCrossRefGoogle Scholar
  44. Salthouse T (1978) The role of memory in the age decline in digit-symbol substitution performance. J Gerontol 33:232PubMedGoogle Scholar
  45. Schmidt W, Roesler A, Kretzschmar K, Ladwig K, Junker R, Berger K (2004) Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc 52:1045–1050PubMedCrossRefGoogle Scholar
  46. Stroop J (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–662CrossRefGoogle Scholar
  47. Tang YP, Wang H, Feng R, Kyin M, Tsien JZ (2001) Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology 41:779–790PubMedCrossRefGoogle Scholar
  48. Tiffin J (1948) Manual for the Purdue Pegboard. Science Research Associates, Chicago (IL)Google Scholar
  49. Tsai SJ, Gau YT, Liu ME, Hsieh CH, Liou YJ, Hong CJ (2008) Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia. Neurosci Lett 433:158–162PubMedCrossRefGoogle Scholar
  50. Xiromerisiou G, Hadjigeorgiou G, Eerola J, Fernandez H, Tsimourtou V, Mandel R, Hellström O, Gwinn-Hardy K, Okun M, Tienari P (2007) BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson’s disease in diverse ethnic groups. Neurosci Lett 415:59–63PubMedCrossRefGoogle Scholar
  51. Zivadinov R, Weinstock-Guttman B, Benedict R, Tamaño-Blanco M, Hussein S, Abdelrahman N, Durfee J, Ramanathan M (2007) Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor. Hum Mol Genet 16:2659PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Katharine R. Laing
    • 1
  • David Mitchell
    • 1
  • Heike Wersching
    • 2
  • Maria E. Czira
    • 2
    • 4
  • Klaus Berger
    • 2
  • Bernhard T. Baune
    • 3
    Email author
  1. 1.Department of Psychology, School of Social Sciences and PsychologyJames Cook UniversityTownsvilleAustralia
  2. 2.Institute of Epidemiology and Social MedicineUniversity of MuensterMuensterGermany
  3. 3.Discipline of Psychiatry, School of MedicineUniversity of AdelaideAdelaideAustralia
  4. 4.Institute of Behavioural SciencesSemmelweis UniversityBudapestHungary

Personalised recommendations