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Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

Abstract

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.

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References

  1. Devlin B, Daniels M, Roeder K . The heritability of IQ. Nature 1997; 388: 468–471.

    Article  CAS  Google Scholar 

  2. McArdle JJ, Prescott CA, Hamagami F, Horn JL . A contempory method for developmental-genetic analysis of age changes in intellectual abilities. Dev Neuropsychol 1998; 14: 69–114.

    Article  Google Scholar 

  3. Schmand B, Smit JH, Geerlings MI, Lindeboom J . The effects of intelligence and education on the development of dementia. A test of the brain reserve hypothesis. Psychol Med 1997; 27: 1337–1344.

    Article  CAS  Google Scholar 

  4. Scarmeas N, Stern Y . Cognitive reserve: implications for diagnosis and prevention of Alzheimer's disease. Curr Neurol Neurosci Rep 2004; 4: 374–380.

    Article  Google Scholar 

  5. Goldberg TE, Weinberger DR . Genes and the parsing of cognitive processes. Trends Cogn Sci 2004; 8: 325–335.

    Article  Google Scholar 

  6. Comings DE, Johnson JP, Gonzalez NS, Huss M, Saucier G, McGue M et al. Association between the adrenergic alpha 2A receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects. Psychiatr Genet 2000; 10: 39–42.

    Article  CAS  Google Scholar 

  7. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  Google Scholar 

  8. Bartres-Faz D, Junque C, Serra-Grabulosa JM, Lopez-Alomar A, Moya A, Bargallo N et al. Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects. Neuroreport 2002; 13: 1121–1125.

    Article  CAS  Google Scholar 

  9. Tsai SJ, Yu YW, Lin CH, Chen TJ, Chen SP, Hong CJ . Dopamine D2 receptor and N-methyl-D-aspartate receptor 2B subunit genetic variants and intelligence. Neuropsychobiology 2002; 45: 128–130.

    Article  CAS  Google Scholar 

  10. Comings DE, Wu S, Rostamkhani M, McGue M, Lacono WG, Cheng LS et al. Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition. Mol Psychiatr 2003; 8: 10–11.

    Article  CAS  Google Scholar 

  11. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  Google Scholar 

  12. Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci USA 2004; 101: 12604–12609.

    Article  CAS  Google Scholar 

  13. DeQuervain DJ, Henke K, Aerni A, Coluccia D, Wollmer MA, Hock CA et al. A functional genetic variation of the 5-HT2a receptor affects human memory. Nat Neurosci 2003; 6: 1141–1142.

    Article  CAS  Google Scholar 

  14. Feskens EJM, Havekes LM, Kalmijn S, de Knijff P, Launer LJ, Kromhout D . Apolipoprotein e4 allele and cognitive decline in elderly men. BMJ 1994; 309: 1202–1206.

    Article  CAS  Google Scholar 

  15. Jonker C, Schmand B, Lindeboom J, Havekes LM, Launer LJ . Association between apolipoprotein E epsilon4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Arch Neurol 1998; 55: 1065–1069.

    Article  CAS  Google Scholar 

  16. Small BJ, Graves AB, McEvoy CL, Crawford FC, Mullan M, Mortimer JA . Is APOE epsilon4 a risk factor for cognitive impairment in normal aging? Neurology 2000; 54: 2082–2088.

    Article  CAS  Google Scholar 

  17. Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ et al. Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer's disease but not in healthy control subjects. Neurology 1998; 50: 355–362.

    Article  CAS  Google Scholar 

  18. Mayeux R, Small SA, Tang M, Tycko B, Stern Y . Memory performance in healthy elderly without Alzheimer's disease: effects of time and apolipoprotein-E. Neurobiol Aging 2001; 22: 683–689.

    Article  CAS  Google Scholar 

  19. Pendleton N, Payton A, van den Boogerd EH, Holland F, Diggle P, Rabbitt PM et al. Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults. Neurosci Lett 2002; 324: 74–76.

    Article  CAS  Google Scholar 

  20. van Kesteren RE, Spencer GE . The role of neurotransmitters in neurite outgrowth and synapse formation. Rev Neurosci 2003; 14: 217–231.

    Article  CAS  Google Scholar 

  21. Meneses A . 5-HT system and cognition. Neurosci Biobehav Rev 1999; 23: 1111–1125.

    Article  CAS  Google Scholar 

  22. Rehman HU, Masson EA . Neuroendocrinology of ageing. Age Ageing 2001; 30: 279–287.

    Article  CAS  Google Scholar 

  23. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    Article  CAS  Google Scholar 

  24. Sen S, Burmeister M, Ghosh D . Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet 2004; 127B: 85–89.

    Article  Google Scholar 

  25. Lin PY, Tsai G . Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatr 2004; 55: 1023–1030.

    Article  CAS  Google Scholar 

  26. Ospina-Duque J, Duque C, Carvajal-Carmona L, Ortiz-Barrientos D, Soto I, Pineda N et al. An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia. Neurosci Lett 2000; 292: 199–202.

    Article  CAS  Google Scholar 

  27. Langley K, Payton A, Hamshere ML, Pay HM, Lawson DC, Turic D et al. No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder. Psychiatr Genet 2003; 13: 107–110.

    PubMed  Google Scholar 

  28. Retz W, Retz-Junginger P, Supprian T, Thome J, Rosler M . Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. Behav Sci Law 2004; 22: 415–425.

    Article  Google Scholar 

  29. Mata I, Arranz MJ, Patino A, Lai T, Beperet M, Sierrasesumaga L et al. Serotonergic polymorphisms and psychotic disorders in populations from North Spain. Am J Med Genet 2004; 126B: 88–94.

    Article  CAS  Google Scholar 

  30. Munafo MR, Clark TG, Moore LR, Payne E, Walton R, Flint J . Genetic polymorphisms and personality in healthy adults: a systematic review and meta-analysis. Mol Psychiatr 2003; 8: 471–484.

    Article  CAS  Google Scholar 

  31. Feinn R, Nellissery M, Kranzler HR . Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 2005; 133: 79–84.

    Article  Google Scholar 

  32. Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM et al. Serotonin transporter SLC6A4LPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 2004; 12: 377–382.

    Article  CAS  Google Scholar 

  33. Lotrich FE, Pollock BG . Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet 2004; 14: 121–129.

    Article  Google Scholar 

  34. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.

    Article  CAS  Google Scholar 

  35. Fiskerstrand CE, Lovejoy EA, Quinn JP . An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett 1999; 458: 171–174.

    Article  CAS  Google Scholar 

  36. MacKenzie A, Quinn J . A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–15255.

    Article  CAS  Google Scholar 

  37. Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B et al. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatr 2004; 55: 1090–1094.

    Article  CAS  Google Scholar 

  38. Heim AW . AH4 Group Test of General Intelligence. NFER-Nelson: Windsor UK, 1970.

    Google Scholar 

  39. Raven JC . The Mill Hill Vocabulary Scale. HK Lewis: London, 1965.

    Google Scholar 

  40. Rabbitt P, Diggle P, Horan M, Pendleton N, Bent N, Abson V et al. The University of Manchester Longitudinal Study of normal healthy old age 1983 through 2003. Aging Neuropsychol Cognition 2004; 11: 245–279.

    Article  Google Scholar 

  41. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    Article  CAS  Google Scholar 

  42. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996; 347: 731–733.

    Article  CAS  Google Scholar 

  43. Binder DA . On the variances of asymptotically normal estimators from complex surveys. Int Statist Rev 1983; 51: 279–292.

    Article  Google Scholar 

  44. Brick JM, Kalton G . Handling missing data in survey research. Statist Methods Med Res 1996; 5: 215–238.

    Article  CAS  Google Scholar 

  45. Rabbitt P, Diggle P, Holland F, McInnes L . Practice and drop-out effects during a 17-year longitudinal study of cognitive aging. J Gerontol B Psychol Sci Soc Sci 2004; 59: P84–P97.

    Article  Google Scholar 

  46. Arivazhagan P, Panneerselvam C . Neurochemical changes related to ageing in the rat brain and the effect of DL-alpha-lipoic acid. Exp Gerontol 2002; 37: 1489–1494.

    Article  CAS  Google Scholar 

  47. Mortensen OV, Thomassen M, Larsen MB, Whittemore SR, Wiborg O . Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells. Brain Res Mol Brain Res 1999; 68: 141–148.

    Article  CAS  Google Scholar 

  48. Vandenberghe R . Language, ageing and neurodegenerative disease. Bull Mem Acad R Med Belg 2004; 159: 161–166.

    PubMed  CAS  Google Scholar 

  49. Subbarao KV, Richardson JS, Ang LC . Autopsy samples of Alzheimer's cortex show increased peroxidation in vitro. J Neurochem 1990; 55: 342–345.

    Article  CAS  Google Scholar 

  50. Harmer CJ, Bhagwagar Z, Perrett DI, Vollm BA, Cowen PJ, Goodwin GM . Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 2003; 28: 148–152.

    Article  CAS  Google Scholar 

  51. Siepmann M, Handel J, Mueck-Weymann M, Kirch W . The effects of moclobemide on autonomic and cognitive functions in healthy volunteers. Pharmacopsychiatry 2004; 37: 81–87.

    Article  CAS  Google Scholar 

  52. Roth BL, Hanizavareh SM, Blum AE . Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 2004; 174: 17–24.

    Article  CAS  Google Scholar 

  53. Bertram L, Tanzi RE . Alzheimer's disease: one disorder, too many genes? Hum Mol Genet 2004; 13: R135–R141.

    Article  CAS  Google Scholar 

  54. Plomin R, McGuffin P . Psychopathology in the postgenomic era. Annu Rev Psychol 2003; 54: 205–228.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Wellcome Trust (Grant number GD045ERG). Blood collection and DNA extraction was partly funded by Research into Ageing.

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Correspondence to A Payton.

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Payton, A., Gibbons, L., Davidson, Y. et al. Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. Mol Psychiatry 10, 1133–1139 (2005). https://doi.org/10.1038/sj.mp.4001733

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Keywords

  • serotonin transporter
  • polymorphism
  • cognition
  • memory
  • genes
  • association

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