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The implication of BDNF Val66Met polymorphism in progression from subjective cognitive decline to mild cognitive impairment and Alzheimer’s disease: a 9-year follow-up study

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Abstract

Brain-derived natriuretic factor (BDNF) Val66Met polymorphism has been frequently reported to be associated with Alzheimer’s disease (AD) with contrasting results. Numerous studies showed that Met allele increased the risk of AD only in women, while other studies have found worse cognitive performance in Val/Val carriers. We aimed to inquire the effects of Val66Met polymorphism on the progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and from MCI to AD and to ascertain if this effect is modulated by demographic and cognitive variables. For this purpose, we followed up 74 subjects (48 SCD, 26 MCI) for a mean time of 9 years. All participants underwent extensive neuropsychological assessment, cognitive reserve estimation, BDNF and apolipoprotein E (ApoE) genotype analysis at baseline. Personality traits and leisure activities were assessed in a subgroup. Each patient underwent clinical–neuropsychological follow-up, during which 18 out of 48 SCD subjects progressed to MCI and 14 out of 26 MCI subjects progressed to AD. We found that Val66Met increased the risk of progression from SCD to MCI and from MCI to AD only in women. Nevertheless, Val/Val carriers who progressed from SCD to MCI had a shorter conversion time compared to Met carriers. We concluded that Val66Met polymorphism might play different roles depending on sex and stage of the disease.

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Abbreviations

SCD:

Subjective cognitive decline

CR:

Cognitive reserve

HDRS:

Hamilton Depression Rating Scale

TIB:

Test di Intelligenza Breve

References

  1. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216. https://doi.org/10.1016/S1474-4422(12)70291-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement 7:280–292. https://doi.org/10.1016/j.jalz.2011.03.003

    Article  Google Scholar 

  3. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement 7:270–279. https://doi.org/10.1016/j.jalz.2011.03.008

    Article  Google Scholar 

  4. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256:183–194. https://doi.org/10.1111/j.1365-2796.2004.01388.x

    Article  CAS  PubMed  Google Scholar 

  5. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M (2014) A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement 10:844–852. https://doi.org/10.1016/j.jalz.2014.01.001

    Article  PubMed  PubMed Central  Google Scholar 

  6. Perrotin A, Mormino EC, Madison CM, Hayenga AO, Jagust WJ (2012) Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals. Arch Neurol 69:223–229. https://doi.org/10.1001/archneurol.2011.666

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stewart R, Godin O, Crivello F, Maillard P, Mazoyer B, Tzourio C, Dufouil C (2011) Longitudinal neuroimaging correlates of subjective memory impairment: 4-year prospective community study. Br J Psychiatry J Ment Sci 198:199–205. https://doi.org/10.1192/bjp.bp.110.078683

    Article  Google Scholar 

  8. Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, Sperling RA, Johnson KA, Rentz DM (2012) Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia 50:2880–2886. https://doi.org/10.1016/j.neuropsychologia.2012.08.011

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B (2014) Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis. Acta Psychiatr Scand 130:439–451. https://doi.org/10.1111/acps.12336

    Article  CAS  PubMed  Google Scholar 

  10. Mendonça MD, Alves L, Bugalho P (2016) From subjective cognitive complaints to dementia: who is at risk?: a systematic review. Am J Alzheimers Dis Other Dement 31:105–114. https://doi.org/10.1177/1533317515592331

    Article  Google Scholar 

  11. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. https://doi.org/10.1146/annurev.neuro.24.1.677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22:123–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McAllister AK, Lo DC, Katz LC (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15:791–803

    Article  CAS  PubMed  Google Scholar 

  14. Zhou X-F, Song X-Y, Zhong J-H, Barati S, Zhou FH-H, Johnson SM (2004) Distribution and localization of pro-brain-derived neurotrophic factor-like immunoreactivity in the peripheral and central nervous system of the adult rat. J Neurochem 91:704–715. https://doi.org/10.1111/j.1471-4159.2004.02775.x

    Article  CAS  PubMed  Google Scholar 

  15. Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276:12660–12666. https://doi.org/10.1074/jbc.M008104200

    Article  CAS  PubMed  Google Scholar 

  16. Mizui T, Ishikawa Y, Kumanogoh H, Lume M, Matsumoto T, Hara T, Yamawaki S, Takahashi M, Shiosaka S, Itami C, Uegaki K, Saarma M, Kojima M (2015) BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc Natl Acad Sci 112:E3067–E3074. https://doi.org/10.1073/pnas.1422336112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang B, Yang C, Ren Q, Zhang J, Chen Q-X, Shirayama Y, Hashimoto K (2016) Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience. Eur Arch Psychiatry Clin Neurosci 266:765–769. https://doi.org/10.1007/s00406-016-0693-6

    Article  PubMed  Google Scholar 

  18. Anastasia A, Deinhardt K, Chao MV, Will NE, Irmady K, Lee FS, Hempstead BL, Bracken C (2013) Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun 4:2490. https://doi.org/10.1038/ncomms3490

    Article  CAS  PubMed  Google Scholar 

  19. Barbey AK, Colom R, Paul E, Forbes C, Krueger F, Goldman D, Grafman J (2014) Preservation of general intelligence following traumatic brain injury: contributions of the Met66 brain-derived neurotrophic factor. PLoS ONE 9:e88733. https://doi.org/10.1371/journal.pone.0088733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63:71–124

    Article  CAS  PubMed  Google Scholar 

  21. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci 105:2711–2716. https://doi.org/10.1073/pnas.0711863105

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hall J, Thomas KL, Everitt BJ (2000) Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3:533–535. https://doi.org/10.1038/75698

    Article  CAS  PubMed  Google Scholar 

  23. Aicardi G, Argilli E, Cappello S, Santi S, Riccio M, Thoenen H, Canossa M (2004) Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc Natl Acad Sci 101:15788–15792. https://doi.org/10.1073/pnas.0406960101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Feng S, Sevigny J, Verma A, Bennett D, Lim YY, Maruff P (2013) Genetic and imaging biomarkers predicting beta-amyloid amyloid—related cognitive decline using the Alzheimer’s disease neuroimaging initiative data. Alzheimer’s Dement 9:P178. https://doi.org/10.1016/j.jalz.2013.05.292

    Article  Google Scholar 

  25. Poo M (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32. https://doi.org/10.1038/35049004

    Article  CAS  PubMed  Google Scholar 

  26. 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. https://doi.org/10.1111/j.1471-4159.2005.03135.x

    Article  CAS  PubMed  Google Scholar 

  27. Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça 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 11:774–780. https://doi.org/10.3109/15622971003797241

    Article  PubMed  Google Scholar 

  28. Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, Baek JH, Park SW, Kim YH (2009) Decreased serum brain-derived neurotrophic factor levels in elderly korean with dementia. Psychiatry Investig 6:299–305. https://doi.org/10.4306/pi.2009.6.4.299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qin X-Y, Cao C, Cawley NX, Liu T-T, Yuan J, Loh YP, Cheng Y (2017) Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease: a meta-analysis study (N = 7277). Mol Psychiatry 22:312–320. https://doi.org/10.1038/mp.2016.62

    Article  CAS  PubMed  Google Scholar 

  30. Borba EM, Duarte JA, Bristot G, Scotton E, Camozzato AL, Chaves MLF (2016) Brain-derived neurotrophic factor serum levels and hippocampal volume in mild cognitive impairment and dementia due to Alzheimer disease. Dement Geriatr Cogn Dis Extra 6:559–567. https://doi.org/10.1159/000450601

    Article  PubMed  PubMed Central  Google Scholar 

  31. Levada OA, Cherednichenko NV, Trailin AV, Troyan AS (2016) Plasma brain-derived neurotrophic factor as a biomarker for the main types of mild neurocognitive disorders and treatment efficacy: a preliminary study. Dis Markers 2016:1–7. https://doi.org/10.1155/2016/4095723

    Article  CAS  Google Scholar 

  32. Weinstein G, Preis SR, Beiser AS, Satizabal CL, Spartano NL, Chen TC, Ramachandran VS, Seshadri S (2015) Associations between BDNF serum levels and Alzheimer’s disease-related measures: the Framingham Study. Alzheimer’s Dement 11:P649. https://doi.org/10.1016/j.jalz.2015.06.948

    Article  Google Scholar 

  33. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269

    Article  CAS  PubMed  Google Scholar 

  34. del Toro D, Canals JM, Gines S, Kojima M, Egea G, Alberch J (2006) Mutant huntingtin impairs the post-golgi trafficking of brain-derived neurotrophic factor but not its Val66Met polymorphism. J Neurosci 26:12748–12757. https://doi.org/10.1523/JNEUROSCI.3873-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bian J-T, Zhang J-W, Zhang Z-X, Zhao H-L (2005) Association analysis of brain-derived neurotrophic factor (BDNF) gene 196 A/G polymorphism with Alzheimer’s disease (AD) in mainland Chinese. Neurosci Lett 387:11–16. https://doi.org/10.1016/j.neulet.2005.07.009

    Article  CAS  PubMed  Google Scholar 

  36. Fehér Á, Juhász A, Rimanóczy Á, Kálmán J, Janka Z (2009) Association between BDNF Val66Met polymorphism and Alzheimer disease, dementia with Lewy bodies, and pick disease. Alzheimer Dis Assoc Disord 23:224–228. https://doi.org/10.1097/WAD.0b013e318199dd7d

    Article  PubMed  Google Scholar 

  37. Matsushita S, Arai H, Matsui T, Yuzuriha T, Urakami K, Masaki T, Higuchi S (2005) Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease. J Neural Transm 112:703–771. https://doi.org/10.1007/s00702-004-0210-3

    Article  CAS  PubMed  Google Scholar 

  38. Nishimura M, Kuno S, Kaji R, Kawakami H (2005) Brain-derived neurotrophic factor gene polymorphisms in Japanese patients with sporadic Alzheimer’s disease, Parkinson’s disease, and multiple system atrophy. Mov Disord 20:1031–1033. https://doi.org/10.1002/mds.20491

    Article  PubMed  Google Scholar 

  39. Nacmias B, Piccini C, Bagnoli S, Tedde A, Cellini E, Bracco L, Sorbi S (2004) Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer’s disease. Neurosci Lett 367:379–383. https://doi.org/10.1016/j.neulet.2004.06.039

    Article  CAS  PubMed  Google Scholar 

  40. Kennedy KM, Reese ED, Horn MM, Sizemore AN, Unni AK, Meerbrey ME, Kalich AG, Rodrigue KM (2015) BDNF val66met polymorphism affects aging of multiple types of memory. Brain Res 1612:104–117. https://doi.org/10.1016/j.brainres.2014.09.044

    Article  CAS  PubMed  Google Scholar 

  41. Boots EA, Schultz SA, Clark LR, Racine AM, Darst BF, Koscik RL, Carlsson CM, Gallagher CL, Hogan KJ, Bendlin BB, Asthana S, Sager MA, Hermann BP, Christian BT, Dubal DB, Engelman CD, Johnson SC, Okonkwo OC (2017) BDNF Val66Met predicts cognitive decline in the Wisconsin registry for Alzheimer’s prevention. Neurology 88:2098–2106. https://doi.org/10.1212/WNL.0000000000003980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington KD, Bourgeat P, Salvado O, Darby D, Snyder PJ, Bush AI, Martins RN, Masters CL, Rowe CC, Nathan PJ, Maruff P, Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group (2013) BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer’s disease. Neurobiol Aging 34:2457–2464. https://doi.org/10.1016/j.neurobiolaging.2013.05.006

    Article  CAS  PubMed  Google Scholar 

  43. Honea RA, Cruchaga C, Perea RD, Saykin AJ, Burns JM, Weinberger DR, Goate AM, Alzheimer’s Disease Neuroimaging Initiative (ADNI) F the ADNI (2013) Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer’s disease neurodegeneration. PLoS ONE 8:e76001. https://doi.org/10.1371/journal.pone.0076001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Weinstein G, Beiser AS, Choi SH, Preis SR, Chen TC, Vorgas D, Au R, Pikula A, Wolf PA, DeStefano AL, Vasan RS, Seshadri S (2014) Serum brain-derived neurotrophic factor and the risk for dementia. JAMA Neurol 71:55. https://doi.org/10.1001/jamaneurol.2013.4781

    Article  PubMed  PubMed Central  Google Scholar 

  45. Erickson KI, Kim JS, Suever BL, Voss MW, Francis BM, Kramer AF (2008) Genetic contributions to age-related decline in executive function: a 10-year longitudinal study of COMT and BDNF polymorphisms. Front Hum Neurosci 2:11. https://doi.org/10.3389/neuro.09.011.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gajewski PD, Hengstler JG, Golka K, Falkenstein M, Beste C (2011) The Met-allele of the BDNF Val66Met polymorphism enhances task switching in elderly. Neurobiol Aging 32:2327.e7–2327.e19. https://doi.org/10.1016/j.neurobiolaging.2011.06.010

    Article  CAS  Google Scholar 

  47. Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ (2006) The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills. Mol Psychiatry 11:505–513. https://doi.org/10.1038/sj.mp.4001799

    Article  CAS  PubMed  Google Scholar 

  48. Nagata T, Shinagawa S, Nukariya K, Yamada H, Nakayama K (2012) Association between BDNF polymorphism (Val66Met) and executive function in patients with amnestic mild cognitive impairment or mild Alzheimer disease. Dement Geriatr Cogn Disord 33:266–272. https://doi.org/10.1159/000339358

    Article  CAS  PubMed  Google Scholar 

  49. Bus BAA, Molendijk ML, Penninx BJWH, Buitelaar JK, Kenis G, Prickaerts J, Elzinga BM, Voshaar RCO (2011) Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 36:228–239. https://doi.org/10.1016/j.psyneuen.2010.07.013

    Article  CAS  PubMed  Google Scholar 

  50. Bus BAA, Tendolkar I, Franke B, de Graaf J, den Heijer M, Buitelaar JK, Oude Voshaar RC (2012) Serum brain-derived neurotrophic factor: determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people. World J Biol Psychiatry 13:39–47. https://doi.org/10.3109/15622975.2010.545187

    Article  PubMed  Google Scholar 

  51. Richards M, Sacker A (2003) Lifetime antecedents of cognitive reserve. J Clin Exp Neuropsychol 25:614–624. https://doi.org/10.1076/jcen.25.5.614.14581

    Article  PubMed  Google Scholar 

  52. Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, Anan Y, Uemura K, Lee S, Park H, Suzuki T (2014) A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci 6:69. https://doi.org/10.3389/fnagi.2014.00069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Trajkovska V, Marcussen AB, Vinberg M, Hartvig P, Aznar S, Knudsen GM (2007) Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Res Bull 73:143–149. https://doi.org/10.1016/j.brainresbull.2007.03.009

    Article  CAS  PubMed  Google Scholar 

  54. Scharfman HE, MacLusky NJ (2006) Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS. Front Neuroendocrinol 27:415–435. https://doi.org/10.1016/j.yfrne.2006.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Barha CK, Liu-Ambrose T, Best JR, Yaffe K, Rosano C (2019) Sex-dependent effect of the BDNF Val66Met polymorphism on executive functioning and processing speed in older adults: evidence from the health ABC study. Neurobiol Aging 74:161–170. https://doi.org/10.1016/j.neurobiolaging.2018.10.021

    Article  CAS  PubMed  Google Scholar 

  56. Fukumoto N, Fujii T, Combarros O, Kamboh MI, Tsai S-J, Matsushita S, Nacmias B, Comings DE, Arboleda H, Ingelsson M, Hyman BT, Akatsu H, Grupe A, Nishimura AL, Zatz M, Mattila KM, Rinne J, Goto Y, Asada T, Nakamura S, Kunugi H (2009) 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. https://doi.org/10.1002/ajmg.b.30986

    Article  Google Scholar 

  57. Li G-D, Bi R, Zhang D-F, Xu M, Luo R, Wang D, Fang Y, Li T, Zhang C, Yao Y-G (2017) Female-specific effect of the BDNF gene on Alzheimer’s disease. Neurobiol Aging 53:192.e11–192.e19. https://doi.org/10.1016/j.neurobiolaging.2016.12.023

    Article  CAS  Google Scholar 

  58. Lin Y, Cheng S, Xie Z, Zhang D (2014) Association of rs6265 and rs2030324 polymorphisms in brain-derived neurotrophic factor gene with Alzheimer’s disease: a meta-analysis. PLoS ONE 9:e94961. https://doi.org/10.1371/journal.pone.0094961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Komulainen P, Pedersen M, Hänninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R (2008) BDNF is a novel marker of cognitive function in ageing women: the DR’s extra study. Neurobiol Learn Mem 90:596–603. https://doi.org/10.1016/j.nlm.2008.07.014

    Article  CAS  PubMed  Google Scholar 

  60. Siuda J, Patalong-Ogiewa M, Żmuda W, Targosz-Gajniak M, Niewiadomska E, Matuszek I, Jędrzejowska-Szypułka H, Rudzińska-Bar M, Rudzińska-Bar M (2017) Cognitive impairment and BDNF serum levels. Neurol Neurochir Pol 51:24–32. https://doi.org/10.1016/j.pjnns.2016.10.001

    Article  PubMed  Google Scholar 

  61. Damirchi A, Hosseini F, Babaei P (2018) Mental training enhances cognitive function and BDNF more than either physical or combined training in elderly women with MCI: a small-scale study. Am J Alzheimer’s Dis Other Dement 33:20–29. https://doi.org/10.1177/1533317517727068

    Article  Google Scholar 

  62. Hong YJ, Yoon B, Shim YS, Kim S-O, Kim HJ, Choi SH, Jeong JH, Yoon SJ, Yang DW, Lee J-H (2015) Predictors of clinical progression of subjective memory impairment in elderly subjects: data from the Clinical Research Centers for Dementia of South Korea (CREDOS). Dement Geriatr Cogn Disord 40:158–165. https://doi.org/10.1159/000430807

    Article  PubMed  Google Scholar 

  63. Canivet A, Albinet CT, Rodríguez-Ballesteros M, Chicherio C, Fagot D, André N, Audiffren M (2017) Interaction between BDNF polymorphism and physical activity on inhibitory performance in the elderly without cognitive impairment. Front Hum Neurosci 11:541. https://doi.org/10.3389/fnhum.2017.00541

    Article  PubMed  PubMed Central  Google Scholar 

  64. Yulug B, Hanoglu L, Khanmammadov E, Duz OA, Polat B, Hanoglu T, Gunal MY, Kilic E (2018) Beyond the therapeutic effect of rTMS in Alzheimer’s disease: a possible neuroprotective role of hippocampal BDNF?: a minireview. Mini Rev Med Chem 18:1479–1485. https://doi.org/10.2174/1389557517666170927162537

    Article  CAS  PubMed  Google Scholar 

  65. Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I (2012) The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex. J Neurosci 32:2410–2421. https://doi.org/10.1523/JNEUROSCI.5205-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ninan I, Bath KG, Dagar K, Perez-Castro R, Plummer MR, Lee FS, Chao MV (2010) The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci 30:8866–8870. https://doi.org/10.1523/JNEUROSCI.1405-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Beeri MS, Sonnen J (2016) Brain BDNF expression as a biomarker for cognitive reserve against Alzheimer disease progression. Neurology 86:702–703. https://doi.org/10.1212/WNL.0000000000002389

    Article  PubMed  Google Scholar 

  68. Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:179–186

    Article  CAS  PubMed  Google Scholar 

  69. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH, Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease—Alzheimer’s & Dementia: The Journal of the Alzheimer’s Associa. In: Alzheimers. Dement. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312027/. Accessed 1 May 2019

  70. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund L-O, Nordberg A, Backman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC (2004) Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 256:240–246. https://doi.org/10.1111/j.1365-2796.2004.01380.x

    Article  CAS  PubMed  Google Scholar 

  71. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Philadelphia

    Book  Google Scholar 

  72. Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299

    Article  CAS  PubMed  Google Scholar 

  73. Crook TH, Feher EP, Larrabee GJ (1992) Assessment of memory complaint in age-associated memory impairment: the MAC-Q. Int Psychogeriatr 4:165–176

    Article  PubMed  Google Scholar 

  74. Bessi V, Mazzeo S, Padiglioni S, Piccini C, Nacmias B, Sorbi S, Bracco L (2018) From subjective cognitive decline to Alzheimer’s disease: the predictive role of neuropsychological assessment, personality traits, and cognitive reserve. a 7-year follow-up study. J Alzheimer’s Dis JAD 63:1523–1535. https://doi.org/10.3233/JAD-171180

    Article  Google Scholar 

  75. Bracco L, Amaducci L, Pedone D, Bino G, Lazzaro MP, Carella F, D’Antona R, Gallato R, Denes G (1990) Italian Multicentre Study on Dementia (SMID): a neuropsychological test battery for assessing Alzheimer’s disease. J Psychiatr Res 24:213–226

    Article  CAS  PubMed  Google Scholar 

  76. Baddeley A, Della Sala S, Papagno C, Spinnler H (1997) Dual-task performance in dysexecutive and nondysexecutive patients with a frontal lesion. Neuropsychology 11:187–194

    Article  CAS  PubMed  Google Scholar 

  77. Brazzelli M, Della Sala S, Laiacona M (1993) Calibration of the Italian version of the Rivermead Behavioural Memory Test: a test for the ecological evaluation of memory. Boll di Psicol Appl 206:33–42

    Google Scholar 

  78. Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci 22:443–447. https://doi.org/10.1007/s100720200003

    Article  CAS  PubMed  Google Scholar 

  79. Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E (1996) Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 17:305–309

    Article  CAS  PubMed  Google Scholar 

  80. Spinnler H, Tognoni G (1987) Standardizzazione e taratura italiana di test neuropsicologici: gruppo italiano per lo studio neuropsicologico dell’invecchiamento, Masson Italia Periodici, Milano

    Google Scholar 

  81. Colombo L, Sartori G, Brivio C (2002) Stima del quoziente intellettivo tramite l’applicazione del TIB (Test Breve di Intelligenza). 3:613–638

  82. Nelson H (1982) National adult reading test (NART): for the assessment of premorbid intelligence in patients with dementia: test manual, Windsor, UK

  83. Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296

    Article  CAS  PubMed  Google Scholar 

  84. Goldberg LR (1993) The structure of phenotypic personality traits. Am Psychol 48:26–34

    Article  CAS  PubMed  Google Scholar 

  85. Costa PT, McCrae RR (1985) The NEO personality inventory: manual, form S and form R. Psychological Assessment Resources, Odessa

    Google Scholar 

  86. Yarnold PR, Stille FC, Martin GJ (1995) Cross-sectional psychometric assessment of the Functional Status Questionnaire: use with geriatric versus nongeriatric ambulatory medical patients. Int J Psychiatry Med 25:305–317. https://doi.org/10.2190/GP4F-WQK9-WRHY-7JM9

    Article  CAS  PubMed  Google Scholar 

  87. Franzmeier N, Ren J, Damm A, Monté-Rubio G, Boada M, Ruiz A, Ramirez A, Jessen F, Düzel E, Rodríguez Gómez O, Benzinger T, Goate A, Karch CM, Fagan AM, McDade E, Buerger K, Levin J, Duering M, Dichgans M, Suárez-Calvet M, Haass C, Gordon BA, Lim YY, Masters CL, Janowitz D, Catak C, Wolfsgruber S, Wagner M, Milz E, Moreno-Grau S, Teipel S, Grothe MJ, Kilimann I, Rossor M, Fox N, Laske C, Chhatwal J, Falkai P, Perneczky R, Lee J-H, Spottke A, Boecker H, Brosseron F, Fliessbach K, Heneka MT, Nestor P, Peters O, Fuentes M, Menne F, Priller J, Spruth EJ, Franke C, Schneider A, Westerteicher C, Speck O, Wiltfang J, Bartels C, Araque Caballero MÁ, Metzger C, Bittner D, Salloway S, Danek A, Hassenstab J, Yakushev I, Schofield PR, Morris JC, Bateman RJ, Ewers M (2019) The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease. Mol Psychiatry. https://doi.org/10.1038/s41380-019-0404-6

    Article  PubMed  PubMed Central  Google Scholar 

  88. Lim YY, Villemagne VL, Laws SM, Pietrzak RH, Snyder PJ, Ames D, Ellis KA, Harrington K, Rembach A, Martins RN, Rowe CC, Masters CL, Maruff P (2015) APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer’s disease. Mol Psychiatry 20:1322–1328. https://doi.org/10.1038/mp.2014.123

    Article  CAS  PubMed  Google Scholar 

  89. Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington K, Bourgeat P, Bush AI, Martins RN, Masters CL, Rowe CC, Maruff P, AIBL Research Group (2014) Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer’s disease: a preliminary study. PLoS ONE 9:e86498. https://doi.org/10.1371/journal.pone.0086498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Forlenza OV, Diniz BS, Teixeira AL, Radanovic M, Talib LL, Rocha NP, Gattaz WF (2015) Lower cerebrospinal fluid concentration of brain-derived neurotrophic factor predicts progression from mild cognitive impairment to Alzheimer’s disease. NeuroMol Med 17:326–332. https://doi.org/10.1007/s12017-015-8361-y

    Article  CAS  Google Scholar 

  91. Xie B, Liu Z, Liu W, Jiang L, Zhang R, Cui D, Zhang Q, Xu S (2017) DNA methylation and tag SNPs of the BDNF gene in conversion of amnestic mild cognitive impairment into Alzheimer’s disease: a cross-sectional cohort study. J Alzheimer’s Dis 58:263–274. https://doi.org/10.3233/JAD-170007

    Article  CAS  Google Scholar 

  92. Laske C, Stransky E, Leyhe T, Eschweiler GW, Maetzler W, Wittorf A, Soekadar S, Richartz E, Koehler N, Bartels M, Buchkremer G, Schott K (2007) BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res 41:387–394. https://doi.org/10.1016/j.jpsychires.2006.01.014

    Article  PubMed  Google Scholar 

  93. Gomar JJ, Conejero-Goldberg C, Huey ED, Davies P, Goldberg TE (2016) Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer’s disease. Neurobiol Aging 39:165–173. https://doi.org/10.1016/j.neurobiolaging.2015.12.004

    Article  CAS  PubMed  Google Scholar 

  94. Krueger F, Pardini M, Huey ED, Raymont V, Solomon J, Lipsky RH, Hodgkinson CA, Goldman D, Grafman J (2011) The Role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury. J Neurosci 31:598–606. https://doi.org/10.1523/JNEUROSCI.1399-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sambataro F, Murty VP, Lemaitre HS, Reed JD, Das S, Goldberg TE, Callicott JH, Weinberger DR, Mattay VS (2010) BNDF modulates normal human hippocampal ageing. Mol Psychiatry 15:116–118. https://doi.org/10.1038/mp.2009.64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mazzeo S, Padiglioni S, Bagnoli S, Bracco L, Nacmias B, Sorbi S, Bessi V (2019) The dual role of cognitive reserve in subjective cognitive decline and mild cognitive impairment: a 7-year follow-up study. J Neurol. https://doi.org/10.1007/s00415-018-9164-5

    Article  PubMed  Google Scholar 

  97. Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11:1006–1012. https://doi.org/10.1016/S1474-4422(12)70191-6

    Article  PubMed  PubMed Central  Google Scholar 

  98. Jeong JH, Na HR, Choi SH, Kim J, Na DL, Seo SW, Chin J, Park SA, Kim E-J, Han HJ, Han S-H, Yoon SJ, Lee J-H, Park KW, Moon SY, Park MH, Choi MS, Han I-W, Lee JH, Lee JS, Shim YS, Kim JY (2016) Group- and home-based cognitive intervention for patients with mild cognitive impairment: a randomized controlled trial. Psychother Psychosom 85:198–207. https://doi.org/10.1159/000442261

    Article  PubMed  Google Scholar 

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Acknowledgements

This research was funded by Ministero della Salute and Regione Toscana (Grants No GR-2010-2316359–Longitudinal clinical-neuropsychological study of subjective memory complaints) and Fondi Ricerca UNIFI 2018.

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  1. Valentina Bessi and Salvatore Mazzeo contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Azienda Ospedaliero-Universitaria Careggi. Largo Brambilla, 3, 50134, Florence, Italy

    Valentina Bessi, Salvatore Mazzeo, Silvia Bagnoli, Sonia Padiglioni, Marco Carraro, Irene Piaceri, Laura Bracco, Sandro Sorbi & Benedetta Nacmias

  2. IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy

    Sandro Sorbi

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  1. Valentina Bessi
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Correspondence to Valentina Bessi.

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All procedures involving experiments on human subjects have been done in accordance with the ethical standards of the Committee on Human Experimentation of the institution in which the experiments were done or in accordance with the Helsinki Declaration of 1975. Specific national laws have been observed.

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Bessi, V., Mazzeo, S., Bagnoli, S. et al. The implication of BDNF Val66Met polymorphism in progression from subjective cognitive decline to mild cognitive impairment and Alzheimer’s disease: a 9-year follow-up study. Eur Arch Psychiatry Clin Neurosci 270, 471–482 (2020). https://doi.org/10.1007/s00406-019-01069-y

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