Skip to main content

Advertisement

SpringerLink
Log in

The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009

  • Review
  • Published:
Neuropsychology Review Aims and scope Submit manuscript

Abstract

Identifying the risk factors for individual differences in age-related cognitive ability and decline is amongst the greatest challenges facing the healthcare of older people. Cognitive impairment caused by “normal ageing” is a major contributor towards overall cognitive deficit in the elderly and a process that exhibits substantial inter- and intra-individual differences. Both cognitive ability and its decline with age are influenced by genetic variation that may act independently or via epistasis/gene-environment interaction. Over the past fourteen years genetic research has aimed to identify the polymorphisms responsible for high cognitive functioning and successful cognitive ageing. Unfortunately, during this period a bewildering array of contrasting reports have appeared in the literature that have implicated over 50 genes with effect sizes ranging from 0.1 to 21%. This review will provide a comprehensive account of the studies performed on cognitively healthy individuals, from the first study conducted in 1995 to present. Based on current knowledge the strong and weak methodologies will be identified and suggestions for future study design will be presented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ahmed, S., Reynolds, B. A., & Weiss, S. (1995). BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronalprecursors. Journal of Neuroscience, 15, 5765–5778.

    CAS  PubMed  Google Scholar 

  • Akaboshi, S., Hogema, B. M., Novelletto, A., Malaspina, P., Salomons, G. S., Maropoulos, G. D., et al. (2003). Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Human Mutation, 22, 442–450.

    CAS  PubMed  Google Scholar 

  • Allen, E. G., Sherman, S., Abramowitz, A., Leslie, M., Novak, G., Rusin, M., et al. (2005). Examination of the effect of the polymorphic CGG repeat in the FMR1 gene on cognitive performance. Behavior Genetics, 35, 435–445.

    PubMed  Google Scholar 

  • Almeida, O. P., Schwab, S. G., Lautenschlager, N. T., Morar, B., Greenop, K. R., Flicker, L., et al. (2008). KIBRA genetic polymorphism influences episodic memory in later life, but does not increase the risk of mild cognitive impairment. Journal of Cellular and Molecular Medicine, 12, 1672–1676.

    CAS  PubMed  Google Scholar 

  • Antonini, A., Leenders, K. L., Reist, H., Thomann, R., Beer, H. F., & Locher, J. (1993). Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and [11C] raclopride. Archives of Neurology, 50, 474–480.

    CAS  PubMed  Google Scholar 

  • Bäckman, L., Nyberg, L., Lindenberger, U., Li, S. C., & Farde, L. (2006). The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neuroscience and Biobehavioral Reviews, 30, 791–807.

    PubMed  Google Scholar 

  • Ball, D., Hill, L., Eley, T. C., Chorney, M. J., Chorney, K., Thompson, L. A., et al. (1998). Dopamine markers and general cognitive ability. NeuroReport, 9, 347–349.

    CAS  PubMed  Google Scholar 

  • Bannon, M. J., & Whitty, C. J. (1997). Age-related and regional differences in dopamine mRNA expression in human midbrain. Neurology, 48, 969–977.

    CAS  PubMed  Google Scholar 

  • Barbaux, S., Plomin, R., & Whitehead, A. S. (2000). Polymorphisms of genes controlling homocysteine/folate metabolism and cognitive function. NeuroReport, 11, 1133–1136.

    CAS  PubMed  Google Scholar 

  • Barnett, J. H., Scoriels, L., & Munafò, M. R. (2008). Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biological Psychiatry, 64, 137–144.

    CAS  PubMed  Google Scholar 

  • Bartrés-Faz, D., Junqué, C., Serra-Grabulosa, J. M., López-Alomar, A., Moya, A., Bargalló, N., et al. (2002). Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects. NeuroReport, 13, 1121–1125.

    PubMed  Google Scholar 

  • Barzilai, N., Atzmon, G., Derby, C. A., Bauman, J. M., & Lipton, R. B. (2006). A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology, 67, 2170–2175.

    CAS  PubMed  Google Scholar 

  • Bathum, L., von Bornemann Hjelmborg, J., Christiansen, L., McGue, M., Jeune, B., & Christensen, K. (2007). Methylenetetrahydrofolate reductase 677C > T and methionine synthase 2756A > G mutations: no impact on survival, cognitive functioning, or cognitive decline in nonagenarians. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 62, 196–201.

    Google Scholar 

  • Batty, G. D., Wennerstad, K. M., Smith, G. D., Gunnell, D., Deary, I. J., & Tynelius, P. (2009). IQ in early adulthood and mortality by middle age: cohort study of 1 million Swedish men. Epidemiology, 20, 100–109.

    PubMed  Google Scholar 

  • Baune, B. T., Ponath, G., Rothermundt, M., Riess, O., Funke, H., & Berger, K. (2008). Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMO-study. Psychoneuroendocrinology, 33, 68–76.

    CAS  PubMed  Google Scholar 

  • Bendixen, M. H., Nexø, B. A., Bohr, V. A., Frederiksen, H., McGue, M., Kølvraa, S., et al. (2004). A polymorphic marker in the first intron of the Werner gene associates with cognitive function in aged Danish twins. Experimental Gerontology, 39, 1101–1107.

    CAS  PubMed  Google Scholar 

  • Benson, M. A., Newey, S. E., Martin-Rendon, E., Hawkes, R., & Blake, D. J. (2001). Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. Journal of Biological Chemistry, 276, 24232–24241.

    CAS  PubMed  Google Scholar 

  • Berman, S. M., & Noble, E. P. (1995). Reduced visuospatial performance in children with the D2 dopamine receptor A1 allele. Behavior Genetics, 25, 45–58.

    CAS  PubMed  Google Scholar 

  • Blasi, P., Boyl, P. P., Ledda, M., Novelletto, A., Gibson, K. M., Jakobs, C., et al. (2002). Structure of human succinic semialdehyde dehydrogenase gene: identification of promoter region and alternatively processed isoforms. Molecular Genetics and Metabolism, 76, 348–362.

    CAS  PubMed  Google Scholar 

  • Blinkhorn, S. (2005). Intelligence: a gender bender. Nature, 438, 31–32.

    CAS  PubMed  Google Scholar 

  • Bochdanovits, Z., Gosso, F. M., van den Berg, L., Rizzu, P., Polderman, T. J., Pardo, L. M., et al. (2009). A Functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly. Behavior Genetics, 39, 15–23.

    PubMed  Google Scholar 

  • Bombin, I., Arango, C., Mayoral, M., Castro-Fornieles, J., Gonzalez-Pinto, A., Gonzalez-Gomez, C., et al. (2008). DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first-episode psychosis adolescents. Am J Med Genet B Neuropsychiatr Genet, 147B, 873–879.

    PubMed  Google Scholar 

  • Borg, J., Henningsson, S., Saijo, T., Inoue, M., Bah, J., Westberg, L., et al. (2009). Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans. Int J Neuropsychopharmacol, 1-10, (in press) PMID: 19500776.

  • Bouchard, T. J., Jr., & McGue, M. (2003). Genetic and environmental influences on human psychological differences. Journal of Neurobiology, 54, 4–45.

    PubMed  Google Scholar 

  • Brandi, M. L., Becherini, L., Gennari, L., Racchi, M., Bianchetti, A., Nacmias, B., et al. (1999). Association of the estrogen receptor alpha gene polymorphisms with sporadic Alzheimer's disease. Biochemical and Biophysical Research Communications, 265, 335–338.

    CAS  PubMed  Google Scholar 

  • Brosh, R. M., Jr., Opresko, P. L., & Bohr, V. A. (2006). Enzymatic mechanism of the WRN helicase/nuclease. Methods in Enzymology, 409, 52–85.

    CAS  PubMed  Google Scholar 

  • Broughton, S., & Partridge, L. (2009). Insulin/IGF-like signalling, the central nervous system and aging. Biochemical Journal, 418, 1–12.

    CAS  PubMed  Google Scholar 

  • Bueller, J. A., Aftab, M., Sen, S., Gomez-Hassan, D., Burmeister, M., & Zubieta, J. K. (2006). BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biological Psychiatry, 59, 812–815.

    CAS  PubMed  Google Scholar 

  • Burdick, K. E., Lencz, T., Funke, B., Finn, C. T., Szeszko, P. R., Kane, J. M., et al. (2006). Genetic variation in DTNBP1 influences general cognitive ability. Human Molecular Genetics, 15, 1563–1568.

    CAS  PubMed  Google Scholar 

  • Butcher, L. M., Meaburn, E., Knight, J., Sham, P. C., Schalkwyk, L. C., Craig, I. W., et al. (2005). SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Human Molecular Genetics, 14, 1315–1325.

    CAS  PubMed  Google Scholar 

  • Butcher, L. M., Davis, O. S., Craig, I. W., & Plomin, R. (2008). Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500 K single nucleotide polymorphism microarrays. Genes Brain and Behavior, 7, 435–446.

    CAS  Google Scholar 

  • Büther, K., Plaas, C., Barnekow, A., & Kremerskothen, J. (2004). KIBRA is a novel substrate for protein kinase Czeta. Biochemical and Biophysical Research Communications, 317, 703–707.

    PubMed  Google Scholar 

  • Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389.

    CAS  PubMed  Google Scholar 

  • Caspi, A., Williams, B., Kim-Cohen, J., Craig, I. W., Milne, B. J., Poulton, R., et al. (2007). Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proceedings of the National Academy of Sciences of the United States of America, 104, 18860–18865.

    CAS  PubMed  Google Scholar 

  • Chen, Z. Y., Patel, P. D., Sant, G., Meng, C. X., Teng, K. K., Hempstead, B. L., et al. (2004). Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. Journal of Neuroscience, 24, 4401–4411.

    CAS  PubMed  Google Scholar 

  • Chorney, M. J., Chorney, K., Seese, N., Owen, M. J., Daniels, J., McGuffin, P., et al. (1998). A quantitative trait locus associated with cognitive ability in children. Psychological Science, 9, 159–166.

    Google Scholar 

  • Comas-Herrera, A., Wittenberg, R., Pickard, L., & Knapp, M. (2007). Cognitive impairment in older people: future demand for long-term care services and the associated costs. International Journal of Geriatric Psychiatry, 22, 1037–1045.

    PubMed  Google Scholar 

  • Comings, D. E., Comings, B. G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., et al. (1991). The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA, 266, 1793–1800.

    CAS  PubMed  Google Scholar 

  • Comings, D. E., Wu, S., Rostamkhani, M., McGue, M., Lacono, W. G., Cheng, L. S., et al. (2003). Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition. Molecular Psychiatry, 8, 10–11.

    CAS  PubMed  Google Scholar 

  • Cook, E. H., Jr., & Scherer, S. W. (2008). Copy-number variations associated with neuropsychiatric conditions. Nature, 455, 919–923.

    CAS  PubMed  Google Scholar 

  • Cope, N., Harold, D., Hill, G., Moskvina, V., Stevenson, J., Holmans, P., et al. (2005). Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. American Journal of Human Genetics, 76, 581–591.

    CAS  PubMed  Google Scholar 

  • Corneveaux, J. J., Liang, W. S., Reiman, E. M., Webster, J. A., Myers, A. J., Zismann, V. L., et al. (2009). Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiol Aging, (in press) PMID: 18789830.

  • Craig, I., & Plomin, R. (2006). Quantitative trait loci for IQ and other complex traits: single-nucleotide polymorphism genotyping using pooled DNA and microarrays. Genes Brain Behav, 5(Suppl 1), 32–37.

    CAS  PubMed  Google Scholar 

  • Crawford, D. C., Acuna, J. M., & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in Medicine, 3, 359–371.

    CAS  PubMed  Google Scholar 

  • Deary, I. J. (2001). Human intelligence differences: a recent history. Trends in Cognitive Sciences, 5, 127–130.

    PubMed  Google Scholar 

  • Deary, I. J., Hamilton, G., Hayward, C., Whalley, L. J., Powell, J., Starr, J. M., et al. (2005). Nicastrin gene polymorphisms, cognitive ability level and cognitive ageing. Neuroscience Letters, 373, 110–114.

    CAS  PubMed  Google Scholar 

  • Deary, I. J., Johnson, W., & Houlihan, L. M. (2009). Genetic foundations of human intelligence. Hum Genet, (in press) PMID: 19294424.

  • Dempster, E. L., Toulopoulou, T., McDonald, C., Bramon, E., Walshe, M., Wickham, H., et al. (2006). Episodic memory performance predicted by the 2 bp deletion in exon 6 of the “alpha 7-like” nicotinic receptor subunit gene. American Journal of Psychiatry, 163, 1832–1834.

    PubMed  Google Scholar 

  • Deshmukh, A., Rodrigue, K. M., Kennedy, K. M., Land, S., Jacobs, B. S., & Raz, N. (2009). Synergistic effects of the MTHFR C677T polymorphism and hypertension on spatial navigation. Biological Psychology, 80, 240–245.

    PubMed  Google Scholar 

  • de Blasi, S., Montesanto, A., Martino, C., Dato, S., De Rango, F., Bruni, A. C., et al. (2009). APOE polymorphism affects episodic memory among non demented elderly subjects. Experimental Gerontology, 44, 224–227.

    PubMed  Google Scholar 

  • de Frias, C. M., Annerbrink, K., Westberg, L., Eriksson, E., Adolfsson, R., & Nilsson, L. G. (2004). COMT gene polymorphism is associated with declarative memory in adulthood and old age. Behavior Genetics, 34, 533–539.

    PubMed  Google Scholar 

  • de Frias, C. M., Annerbrink, K., Westberg, L., Eriksson, E., Adolfsson, R., & Nilsson, L. G. (2005). Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults. Journal of Cognitive Neuroscience, 17, 1018–1025.

    PubMed  Google Scholar 

  • de Lau, L. M., van Meurs, J. B., Uitterlinden, A. G., Smith, A. D., Refsum, H., Johnston, C.,et al. (2009). Genetic variation in homocysteine metabolism, cognition, and white matter lesions. Neurobiol Aging, 2009, (in press) PMID: 19019492.

  • de Quervain, D. J., Henke, K., Aerni, A., Coluccia, D., Wollmer, M. A., Hock, C., et al. (2003). A functional genetic variation of the 5-HT2a receptor affects human memory. Nature Neuroscience, 6, 1141–1142.

    PubMed  Google Scholar 

  • de Rango, F., Leone, O., Dato, S., Novelletto, A., Bruni, A. C., Berardelli, M., et al. (2008). Cognitive functioning and survival in the elderly: the SSADH C538T polymorphism. Annals of Human Genetics, 72, 630–635.

    PubMed  Google Scholar 

  • Dick, D. M., Aliev, F., Kramer, J., Wang, J. C., Hinrichs, A., Bertelsen, S., et al. (2007). Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence. Behavior Genetics, 37, 265–272.

    PubMed  Google Scholar 

  • Dickstein, D. L., Kabaso, D., Rocher, A. B., Luebke, J. I., Wearne, S. L., & Hof, P. R. (2007). Changes in the structural complexity of the aged brain. Aging Cell, 6, 275–284.

    CAS  PubMed  Google Scholar 

  • Dröge, W., & Schipper, H. M. (2007). Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell, 6, 361–370.

    PubMed  Google Scholar 

  • Durga, J., van Boxtel, M. P., Schouten, E. G., Bots, M. L., Kok, F. J., & Verhoef, P. (2006). Folate and the methylenetetrahydrofolate reductase 677C− > T mutation correlate with cognitive performance. Neurobiology of Aging, 27, 334–343.

    CAS  PubMed  Google Scholar 

  • Duron, E., & Hanon, O. (2008). Vascular risk factors, cognitive decline, and dementia. Vascular Health and Risk Management, 4, 363–381.

    CAS  PubMed  Google Scholar 

  • Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.

    CAS  PubMed  Google Scholar 

  • Epstein, C. J., Martin, G. M., Schultz, A. L., & Motulsky, A. G. (1966). Werner’s syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine, 45, 177–221.

    CAS  PubMed  Google Scholar 

  • Erickson, K. I., Kim, J. S., Suever, B. L., Voss, M. W., Francis, B. M., & Kramer, A. F. (2008). Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms. Frontiers in Human Neuroscience, 2, 11.

    PubMed  Google Scholar 

  • Espeseth, T., Greenwood, P. M., Reinvang, I., Fjell, A. M., Walhovd, K. B., Westlye, L. T., et al. (2006). Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults. Cognitive Affective & Behavioral Neuroscience, 6, 31–43.

    Google Scholar 

  • Finkel, D., Reynolds, C. A., McArdle, J. J., & Pedersen, N. L. (2005). The longitudinal relationship between processing speed and cognitive ability: genetic and environmental influences. Behavior Genetics, 35, 535–549.

    PubMed  Google Scholar 

  • Finkel, D., Reynolds, C. A., Berg, S., & Pedersen, N. L. (2006). Surprising lack of sex differences in normal cognitive aging in twins. International Journal of Aging and Human Development, 62, 335–357.

    PubMed  Google Scholar 

  • Finkel, D., Reynolds, C. A., McArdle, J. J., & Pedersen, N. L. (2007). Age changes in processing speed as a leading indicator of cognitive aging. Psychology and Aging, 22, 558–568.

    PubMed  Google Scholar 

  • Finkel, D., Reynolds, C. A., McArdle, J. J., Hamagami, F., & Pedersen, N. L. (2009). Genetic Variance in Processing Speed Drives Variation in Aging of Spatial and Memory Abilities. Developmental Psychology, 45, 820–834.

    PubMed  Google Scholar 

  • Fisher, P. J., Turic, D., Williams, N. M., McGuffin, P., Asherson, P., Ball, D., et al. (1999). DNA pooling identifies QTLs on chromosome 4 for general cognitive ability in children. Human Molecular Genetics, 8, 915–922.

    CAS  PubMed  Google Scholar 

  • Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 313, 1419–1420.

    Google Scholar 

  • Francks, C., Paracchini, S., Smith, S. D., Richardson, A. J., Scerri, T. S., Cardon, L. R., et al. (2004). A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. Am J Hum Genet, 75, 1046 –1058.

    Google Scholar 

  • Frodl, T., Schule, C., Schmitt, G., Born, C., Baghai, T., Zill, P., et al. (2007). Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Archives of General Psychiatry, 64, 410–416.

    CAS  PubMed  Google Scholar 

  • Froehlich, T. E., Lanphear, B. P., Dietrich, K. N., Cory-Slechta, D. A., Wang, N., & Kahn, R. S. (2007). Interactive effects of a DRD4 polymorphism, lead, and sex on executive functions in children. Biological Psychiatry, 62, 243–249.

    CAS  PubMed  Google Scholar 

  • Fuster, J. M. (2001). The prefrontal cortex - an update: Time is of the essence. Neuron, 30, 319–333.

    CAS  PubMed  Google Scholar 

  • Gelernter, J., Yu, Y., Weiss, R., Brady, K., Panhuysen, C., Yang, B. Z., et al. (2006). Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Human Molecular Genetics, 15, 3498–3507.

    CAS  PubMed  Google Scholar 

  • Gibson, K. M. (2005). Gamma-hydroxybutyric aciduria: a biochemist’s education from a heritable disorder of GABA metabolism. Journal of Inherited Metabolic Disease, 28, 247–265.

    CAS  PubMed  Google Scholar 

  • Glymour, M. M., Weuve, J., & Chen, J. T. (2008). Methodological challenges in causal research on racial and ethnic patterns of cognitive trajectories: measurement, selection, and bias. Neuropsychology Review, 18, 194–213.

    PubMed  Google Scholar 

  • Goldman-Rakic, P. S., Muly, E. C., & Williams, G. V. (2000). D(1) receptors in prefrontal cells and circuits. Brain Research Brain Research Reviews, 31, 295–301.

    CAS  PubMed  Google Scholar 

  • Gosso, M. F., van Belzen, M., de Geus, E. J., Polderman, J. C., Heutink, P., Boomsma, D. I., et al. (2006a). Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families. Genes Brain and Behavior, 5, 577–584.

    CAS  Google Scholar 

  • Gosso, M. F., de Geus, E. J., van Belzen, M. J., Polderman, T. J., Heutink, P., Boomsma, D. I., et al. (2006b). The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Molecular Psychiatry, 11, 878–886.

    CAS  PubMed  Google Scholar 

  • Gosso, F. M., de Geus, E. J., Polderman, T. J., Boomsma, D. I., Posthuma, D., & Heutink, P. (2007). Exploring the functional role of the CHRM2 gene in human cognition: results from a dense genotyping and brain expression study. BMC Medical Genetics, 8, 66.

    PubMed  Google Scholar 

  • Gosso, M. F., de Geus, E. J., Polderman, T. J., Boomsma, D. I., Heutink, P., & Posthuma, D. (2008). Common variants underlying cognitive ability: further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts. Genes Brain and Behavior, 7, 355–364.

    CAS  Google Scholar 

  • Göthert, M., Propping, P., Bönisch, H., Brüss, M., & Nöthen, M. M. (1998). Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role. Annals of the New York Academy of Sciences, 861, 26–30.

    PubMed  Google Scholar 

  • Goto, M. (1997). Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal aging. Mechanisms of Ageing and Development, 98, 239–254.

    CAS  PubMed  Google Scholar 

  • Goto, M., Miller, R. W., Ishikawa, Y., & Sugano, H. (1996). Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiology, Biomarkers and Prevention, 5, 239–246.

    CAS  PubMed  Google Scholar 

  • Greenwood, P. M., Lin, M. K., Sundararajan, R., Fryxell, K. J., & Parasuraman, R. (2009). Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory. Proceedings of the National Academy of Sciences of the United States of America, 106, 3633–3638.

    CAS  PubMed  Google Scholar 

  • Gustafson, D., Rothenberg, E., Blennow, K., Steen, B., & Skoog, I. (2003). An 18-year follow-up of overweight and risk of Alzheimer disease. Archives of Internal Medicine, 163, 1524–1528.

    PubMed  Google Scholar 

  • Hall, J., Whalley, H. C., Job, D. E., Baig, B. J., McIntosh, A. M., Evans, K. L., et al. (2006). A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nature Neuroscience, 9, 1477–1478.

    CAS  PubMed  Google Scholar 

  • Hansell, N. K., James, M. R., Duffy, D. L., Birley, A. J., Luciano, M., Geffen, G. M., et al. (2007). Effect of the BDNF V166M polymorphism on working memory in healthy adolescents. Genes Brain and Behavior, 6, 260–268.

    CAS  Google Scholar 

  • Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology, 11, 298–300.

    CAS  PubMed  Google Scholar 

  • Harris, S. E., Fox, H., Wright, A. F., Hayward, C., Starr, J. M., Whalley, L. J., et al. (2006). The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills. Molecular Psychiatry, 11, 505–513.

    CAS  PubMed  Google Scholar 

  • Harris, S. E., Fox, H., Wright, A. F., Hayward, C., Starr, J. M., Whalley, L. J., et al. (2007). A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition. BMC Genetics, 8, 43.

    PubMed  Google Scholar 

  • Hattersley, A. T., & McCarthy, M. I. (2005). What makes a good genetic association study? Lancet, 366, 1315–1323.

    PubMed  Google Scholar 

  • Hattiangady, B., Rao, M. S., Shetty, G. A., & Shetty, A. K. (2005). Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Experimental Neurology, 195, 353–371.

    CAS  PubMed  Google Scholar 

  • Heiman, G. A., Hodge, S. E., Gorroochurn, P., Zhang, J., & Greenberg, D. A. (2004). Effect of population stratification on case-control association studies. I. Elevation in false positive rates and comparison to confounding risk ratios (a simulation study). Human Heredity, 58, 30–39.

    PubMed  Google Scholar 

  • Hill, L., Chorney, M. J., Lubinski, D., Thompson, L. A., & Plomin, R. (2002). A quantitative trait locus not associated with cognitive ability in children: a failure to replicate. Psychological Science, 13, 561–562.

    PubMed  Google Scholar 

  • Houlihan, L. M., Harris, S. E., Luciano, M., Gow, A. J., Starr, J. M., Visscher, P. M., et al. (2009). Replication study of candidate genes for cognitive abilities: the Lothian Birth Cohort 1936. Genes Brain and Behavior, 8, 238–247.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Huang, W., Payne, T. J., Ma, J. Z., Beuten, J., Dupont, R. T., Inohara, N., et al. (2009a). Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African-American sample. Neuropsychopharmacology, 34, 319–330.

    CAS  PubMed  Google Scholar 

  • Huang, L., Li, Y., Singleton, A. B., Hardy, J. A., Abecasis, G., Rosenberg, N. A., et al. (2009b). Genotype-imputation accuracy across worldwide human populations. American Journal of Human Genetics, 84, 235–250.

    CAS  PubMed  Google Scholar 

  • Huppert, F. A., Cabelli, S. T., & Matthews, F. E. (2005). MRC Cognitive Function and Ageing Study. Brief cognitive assessment in a UK population sample — distributional properties and the relationship between the MMSE and an extended mental state examination. BMC Geriatric, 5, 7.

    Google Scholar 

  • Iizuka, Y., Sei, Y., Weinberger, D. R., & Straub, R. E. (2007). Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. Journal Neuroscience, 27, 12390–12395.

    CAS  Google Scholar 

  • Irwing, P., & Lynn, R. (2005). Sex differences in means and variability on the progressive matrices in university students: a meta-analysis. British Journal of Psychology, 96, 505–524.

    PubMed  Google Scholar 

  • Irwing, P., & Lynn, R. (2006). Intelligence: is there a sex difference in IQ scores? Nature, 442, E1–E2.

    CAS  PubMed  Google Scholar 

  • Izumi, A., Iijima, Y., Noguchi, H., Numakawa, T., Okada, T., Hori, H., et al. (2008). Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions. Neuropsychopharmacology, 33, 3237–3245.

    CAS  PubMed  Google Scholar 

  • Johannsen, S., Duning, K., Pavenstädt, H., Kremerskothen, J., & Boeckers, T. M. (2008). Temporal-spatial expression and novel biochemical properties of the memory-related protein KIBRA. Neuroscience, 155, 1165–1173.

    CAS  PubMed  Google Scholar 

  • Johnson, W., Harris, S. E., Collins, P., Starr, J. M., Whalley, L. J., & Deary, I. J. (2007). No association of CETP genotype with cognitive function or age-related cognitive change. Neuroscience Letters, 420, 189–192.

    CAS  PubMed  Google Scholar 

  • Johnson, W., Harris, S. E., Starr, J. M., Whalley, L. J., & Deary, I. J. (2008). PPARG Pro12Ala genotype and risk of cognitive decline in elders? Maybe with diabetes. Neuroscience Letters, 434, 50–55.

    CAS  PubMed  Google Scholar 

  • Kaasinen, V., Vilkman, H., Hietala, J., Nagren, K., Helenius, H., Olsson, H., et al. (2000). Age-related D2/D3 receptor loss in extrastriatal regions of the human brain. Neurobiology of Aging, 21, 683–688.

    CAS  PubMed  Google Scholar 

  • Kachiwala, S. J., Harris, S. E., Wright, A. F., Hayward, C., Starr, J. M., Whalley, L. J., et al. (2005). Genetic influences on oxidative stress and their association with normal cognitive ageing. Neuroscience Letters, 386, 116–120.

    CAS  PubMed  Google Scholar 

  • Kavvoura, F. K., & Ioannidis, J. P. (2008). Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls. Human Genetics, 123, 1–14.

    PubMed  Google Scholar 

  • Kearney-Schwartz, A., Rossignol, P., Bracard, S., Felblinger, J., Fay, R., Boivin, J. M., et al. (2009). Vascular structure and function is correlated to cognitive performance and white matter hyperintensities in older hypertensive patients with subjective memory complaints. Stroke, 40, 1229–1236.

    PubMed  Google Scholar 

  • Kim, J. H., Ellwood, P. E., & Asher, M. I. (2009). Diet and asthma: looking back, moving forward. Respiratory Research, 10, 49.

    PubMed  Google Scholar 

  • Kirov, G., Grozeva, D., Norton, N., Ivanov, D., Mantripragada, K. K., Holmans, P., et al. (2009). Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics, 18, 1497–1503.

    CAS  PubMed  Google Scholar 

  • Kloppenborg, R. P., van den Berg, E., Kappelle, L. J., & Biessels, G. J. (2008). Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. European Journal of Pharmacology, 585, 97–108.

    CAS  PubMed  Google Scholar 

  • Komulainen, P., Pedersen, M., Hänninen, T., Bruunsgaard, H., Lakka, T. A., Kivipelto, M., et al. (2008). BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA Study. Neurobiology of Learning and Memory, 90, 596–603.

    CAS  PubMed  Google Scholar 

  • Kudlow, B. A., Kennedy, B. K., & Monnat, R. J., Jr. (2007). Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature Reviews Molecular Cell Biology, 8, 394–404.

    CAS  PubMed  Google Scholar 

  • Kumar, R. A., & Christian, S. L. (2009). Genetics of autism spectrum disorders. Current Neurology and Neuroscience Reports, 9, 188–197.

    PubMed  Google Scholar 

  • Kuningas, M., Slagboom, P. E., Westendorp, R. G., & van Heemst, D. (2006). Impact of genetic variations in the WRN gene on age related pathologies and mortality. Mechanisms of Ageing and Development, 127, 307–313.

    CAS  PubMed  Google Scholar 

  • Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y. M., Szumlanski, C. L., & Weinshilboum, R. M. (1996). Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics, 6, 243–250.

    CAS  PubMed  Google Scholar 

  • Lambert, J. C., Ferreira, S., Gussekloo, J., Christiansen, L., Brysbaert, G., Slagboom, E., et al. (2007). Evidence for the association of the S100beta gene with low cognitive performance and dementia in the elderly. Molecular Psychiatry, 12, 870–880.

    CAS  PubMed  Google Scholar 

  • Lin, B. K., Clyne, M., Walsh, M., Gomez, O., Yu, W., Gwinn, M., et al. (2006). Tracking the epidemiology of human genes in the literature: the HuGE Published Literature database. American Journal of Epidemiology, 164, 1–4.

    PubMed  Google Scholar 

  • Lind, P. A., Luciano, M., Horan, M., Marioni, R. E., Wright, M. J., Montgomery, G. W., et al. (2009). No association between cholinergic muscarinic receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples. Beh Genet, (in press) PMID: 19418213.

  • Lindenberger, U., Nagel, I. E., Chicherio, C., Li, S. C., Heekeren, H. R., & Bäckman, L. (2008). Age-related decline in brain resources modulates genetic effects on cognitive functioning. Frontiers in Neuroscience, 2, 234–244.

    CAS  PubMed  Google Scholar 

  • Luciano, M., Lind, P. A., Duffy, D. L., Castles, A., Wright, M. J., Montgomery, G. W., et al. (2007). A haplotype spanning KIAA0319 and TTRAP is associated with normal variation in reading and spelling ability. Biological Psychiatry, 62, 811–817.

    CAS  PubMed  Google Scholar 

  • Luciano, M., Lind, P. A., Deary, I. J., Payton, A., Posthuma, D., Butcher, L. M., et al. (2008). Testing replication of a 5-SNP set for general cognitive ability in six population samples. European Journal of Human Genetics, 16, 1388–1395.

    CAS  PubMed  Google Scholar 

  • Luciano, M., Miyajima, F., Lind, P. A., Bates, T. C., Horan, M., Harris, S. E., et al. (2009a). Variation in the Dysbindin gene and normal cognitive function in three independent population samples. Genes Brain and Behavior, 8, 218–227.

    CAS  Google Scholar 

  • Luciano, M., Gow, A. J., Taylor, M. D., Hayward, C., Harris, S. E., Campbell, H., et al. (2009b). Apolipoprotein E is not related to memory abilities at 70 years of age. Behavior Genetics, 39, 6–14.

    PubMed  Google Scholar 

  • Luo, Y., & Roth, G. S. (2000). The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antiox Redox Signal, 2, 449–460.

    CAS  Google Scholar 

  • Ma, S. Y., Ciliax, B. J., Stebbins, G., Jaffar, S., Joyce, J. N., Cochran, E. J., et al. (1999). Dopamine transporter-immunoreactive neurons decrease with age in the human substantia nigra. Journal of Comparative Neurology, 409, 25–37.

    CAS  PubMed  Google Scholar 

  • Marshall, F. H. (2008). The role of GABA(B) receptors in the regulation of excitatory neurotransmission. Results and Problems in Cell Differentiation, 44, 87–98.

    CAS  PubMed  Google Scholar 

  • Maruyama, H., Toji, H., Harrington, C. R., Sasaki, K., Izumi, Y., Ohnuma, T., et al. (2000). Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease. Archives of Neurology, 57, 236–240.

    CAS  PubMed  Google Scholar 

  • Mattson, M. P., Chan, S. L., & Duan, W. (2002). Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiological Reviews, 82, 637–672.

    CAS  PubMed  Google Scholar 

  • McAllister, T. W., Flashman, L. A., Harker-Rhodes, C., Tyler, A. L., Moore, J. H., Saykin, A. J., et al. (2008). Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: a replication and extension study. Brain Injury, 22, 705–714.

    PubMed  Google Scholar 

  • McArdle, J. J., Prescott, C. A., Hamagami, F., & Horn, J. L. (1998). A contempory method for developmental-genetic analysis of age changes in intellectual abilities. Developmental Neuropsychology, 14, 69–114.

    Article  Google Scholar 

  • McGue, M., & Christensen, K. (2002). The heritability of level and rate-of-change in cognitive functioning in Danish twins aged 70 years and older. Experimental Aging Research, 28, 435–451.

    PubMed  Google Scholar 

  • MacKenzie, A., & Quinn, J. (1999). A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proceedings of the National Academy of Sciences of the United States of America, 96, 15251–15255.

    CAS  PubMed  Google Scholar 

  • Meaburn, E. L., Harlaar, N., Craig, I. W., Schalkwyk, L. C., & Plomin, R. (2008). Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100 K SNP microarrays in a sample of 5760 children. Molecular Psychiatry, 13, 729–740.

    CAS  PubMed  Google Scholar 

  • Meneses, A. (1999). 5-HT system and cognition. Neuroscience and Biobehavioral Reviews, 23, 1111–1125.

    CAS  PubMed  Google Scholar 

  • Meyer-Lindenberg, A., Straub, R. E., Lipska, B. K., Verchinski, B. A., Goldberg, T., Callicott, J. H., et al. (2007). Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. Journal of Clinical Investigation, 117, 672–682.

    CAS  PubMed  Google Scholar 

  • Miyajima, F., Ollier, W., Mayes, A., Jackson, A., Thacker, N., Rabbitt, P., et al. (2008a). Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav, 7, 411–417.

    CAS  PubMed  Google Scholar 

  • Miyajima, F., Quinn, J. P., Horan, M., Pickles, A., Ollier, W. E., Pendleton, N., et al. (2008b). Additive effect of BDNF and REST polymorphisms is associated with improved general cognitive ability. Genes Brain and Behavior, 7, 714–719.

    CAS  Google Scholar 

  • Moises, H. W., Frieboes, R. M., Spelzhaus, P., Yang, L., Köhnke, M., Herden-Kirchhoff, O., et al. (2001). No association between dopamine D2 receptor gene (DRD2) and human intelligence. Journal of Neural Transmission, 108, 115–121.

    CAS  PubMed  Google Scholar 

  • Morales, E., Sunyer, J., Castro-Giner, F., Estivill, X., Julvez, J., Ribas-Fitó, N., et al. (2008). Influence of glutathione S-transferase polymorphisms on cognitive functioning effects induced by p, p’-DDT among preschoolers. Environmental Health Perspectives, 116, 1581–1585.

    CAS  PubMed  Google Scholar 

  • Mori, E., Hirono, N., Yamashita, H., Imamura, T., Ikejiri, Y., Ikeda, M., et al. (1997). Premorbid brain size as a determinant of reserve capacity against intellectual decline in Alzheimer’s disease. American Journal of Psychiatry, 154, 18–24.

    CAS  PubMed  Google Scholar 

  • Morrison, J. H., & Hof, P. R. (1997). Life and death of neurons in the aging brain. Science, 278, 412–419.

    CAS  PubMed  Google Scholar 

  • Nacmias, B., Bessi, V., Bagnoli, S., Tedde, A., Cellini, E., Piccini, C., et al. (2008). KIBRA gene variants are associated with episodic memory performance in subjective memory complaints. Neuroscience Letters, 436, 145–147.

    CAS  PubMed  Google Scholar 

  • Nagel, I. E., Chicherio, C., Li, S. C., von Oertzen, T., Sander, T., Villringer, A., et al. (2008). Human aging magnifies genetic effects on executive functioning and working memory. Frontiers in Human Neuroscience, 2, 1.

    PubMed  Google Scholar 

  • Need, A. C., Attix, D. K., McEvoy, J. M., Cirulli, E. T., Linney, K. N., Wagoner, A. P., et al. (2008). Failure to replicate effect of Kibra on human memory in two large cohorts of European origin. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 667–668.

    CAS  Google Scholar 

  • Neubauer, A. C., Grabner, R. H., Fink, A., & Neuper, C. (2005). Intelligence and neural efficiency: further evidence of the influence of task content and sex on the brain-IQ relationship. Brain Research Cognitive Brain Research, 25, 217–225.

    PubMed  Google Scholar 

  • Neville, M. J., Johnstone, E. C., & Walton, R. T. (2004). Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Human Mutation, 23, 540–545.

    CAS  PubMed  Google Scholar 

  • Nicodemus, K. K., Luna, A., Vakkalanka, R., Goldberg, T., Egan, M., Straub, R. E., et al. (2006). Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Molecular Psychiatry, 11, 1062–1065.

    CAS  PubMed  Google Scholar 

  • Okada, T., Hashimoto, R., Numakawa, T., Iijima, Y., Kosuga, A., Tatsumi, M., et al. (2006). A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity. Molecular Psychiatry, 11, 695–703.

    CAS  PubMed  Google Scholar 

  • Opgen-Rhein, C., Lencz, T., Burdick, K. E., Neuhaus, A. H., DeRosse, P., Goldberg, T. E., et al. (2008). Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance. Schizophrenia Research, 103, 169–177.

    PubMed  Google Scholar 

  • Papassotiropoulos, A., Henke, K., Aerni, A., Coluccia, D., Garcia, E., Wollmer, M. A., et al. (2005). Age-dependent effects of the 5-hydroxytryptamine-2a-receptor polymorphism (His452Tyr) on human memory. NeuroReport, 16, 839–842.

    CAS  PubMed  Google Scholar 

  • Papassotiropoulos, A., Stephan, D. A., Huentelman, M. J., Hoerndli, F. J., Craig, D. W., Pearson, J. V., et al. (2006). Common Kibra alleles are associated with human memory performance. Science, 314, 475–478.

    CAS  PubMed  Google Scholar 

  • Parasuraman, R., Greenwood, P. M., Kumar, R., & Fossella, J. (2005). Beyond heritability: neurotransmitter genes differentially modulate visuospatial attention and working memory. Psychological Science, 16, 200–207.

    PubMed  Google Scholar 

  • Payton, A., Holland, F., Diggle, P., Rabbitt, P., Horan, M., Davidson, Y., et al. (2003). Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population. Molecular Psychiatry, 8, 14–18.

    CAS  PubMed  Google Scholar 

  • Payton, A., Gibbons, L., Davidson, Y., Ollier, W., Rabbitt, P., Worthington, J., et al. (2005). Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a non-demented elderly population. Molecular Psychiatry, 10, 1133–1139.

    CAS  PubMed  Google Scholar 

  • Payton, A., Horan, M., Davidson, Y., Gibbons, L., Ollier, W., Rabbitt, P., et al. (2006). Influence and interactions of cathepsin D, HLA-DRB1 and APOE on cognitive abilities in an older non-demented population. Genes Brain and Behavior, 5, 23–31.

    CAS  Google Scholar 

  • Peper, J. S., Brouwer, R. M., Boomsma, D. I., Kahn, R. S., & Hulshoff, H. E. (2007). Genetic influences on human brain structure: a review of brain imaging studies in twins. Human Brain Mapping, 28, 464–473.

    PubMed  Google Scholar 

  • Peters, K., Wiltshire, S., Henders, A. K., Dragović, M., Badcock, J. C., Chandler, D., et al. (2008). Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics , 147B, 1159–1166.

    CAS  Google Scholar 

  • Petrill, S. A., Plomin, R., McClearn, G. E., Smith, D. L., Vignetti, S., Chorney, M. J., et al. (1997). No association between general cognitive ability and the A1 allele of the D2 dopamine receptor gene. Behavior Genetics, 27, 29–31.

    CAS  PubMed  Google Scholar 

  • Petryshen, T. L., Kaplan, B. J., Liu, M. F., & Field, L. L. (2000). Absence of significant linkage between phonological coding dyslexia and chromosome 6p23-21.3, as determined by use of quantitative-trait methods: confirmation of qualitative analyses. American Journal of Human Genetics, 66, 708–714.

    CAS  PubMed  Google Scholar 

  • Pezawas, L., Verchinski, B. A., Mattay, V. S., Callicott, J. H., Kolachana, B. S., Straub, R. E., et al. (2004). The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. Journal of Neuroscience, 24, 10099–10102.

    CAS  PubMed  Google Scholar 

  • Pfefferbaum, A., Sullivan, E. V., Swan, G. E., & Carmelli, D. (2000). Brain structure in men remains highly heritable in the seventh and eighth decades of life. Neurobiology of Aging, 21, 63–74.

    CAS  PubMed  Google Scholar 

  • Pierce, G. L., Lesniewski, L. A., Lawson, B. R., Beske, S. D., & Seals, D. R. (2009). Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation, 119, 1284–1292.

    CAS  PubMed  Google Scholar 

  • Pietiläinen, O. P., Paunio, T., Loukola, A., Tuulio-Henriksson, A., Kieseppä, T., Thompson, P., et al. (2009). Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 150B, 683–692.

    Google Scholar 

  • Platko, J. V., Wood, F. B., Pelser, I., Meyer, M., Gericke, G. S., O’Rourke, J., et al. (2008). Association of reading disability on chromosome 6p22 in the Afrikaner population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 1278–1287.

    Google Scholar 

  • Plomin, R. (2003). Genetics, genes, genomics and g. Molecular Psychiatry, 8, 1–5.

    CAS  PubMed  Google Scholar 

  • Plomin, R., Turic, D. M., Hill, L., Turic, D. E., Stephens, M., Williams, J., et al. (2004). A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability. Molecular Psychiatry, 9, 582–586.

    CAS  PubMed  Google Scholar 

  • Poo, M. M. (2001). Neurotrophins as synaptic modulators. Nature Reviews Neuroscience, 2, 24–32.

    CAS  PubMed  Google Scholar 

  • Posthuma, D., Baaré, W. F., Hulshoff Pol, H. E., Kahn, R. S., Boomsma, D. I., & De Geus, E. J. (2003). Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Research, 6, 131–139.

    PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Qi, L., & Cho, Y. A. (2008). Gene-environment interaction and obesity. Nutrition Reviews, 66, 684–694.

    PubMed  Google Scholar 

  • Rabbitt, P., & Lowe, C. (2000). Patterns of cognitive ageing. Psychological Research, 63, 308–316.

    CAS  PubMed  Google Scholar 

  • Rabbitt, P., Diggle, P., Holland, F., & McInnes, L. (2004a). Practice and drop-out effects during a 17-year longitudinal study of cognitive aging. Journal of Gerontology B Psychological Sciences Social Sciences, 59, 84–97.

    Google Scholar 

  • Rabbitt, P. M. A., Diggle, P., Holland, F., McInnes, L., Bent, N., Abson, V., et al. (2004b). The University of Manchester longitudinal study of cognition in normal healthy old age, 1983 through 2003. Aging, Neuropsychology and Cognition, 11, 245–279.

    Google Scholar 

  • Ravaglia, G., Forti, P., Maioli, F., Scali, R. C., Arnone, G., Talerico, T., et al. (2004). Common polymorphisms in methylenetetrahydrofolate reductase (MTHFR): relationships with plasma homocysteine concentrations and cognitive status in elderly northern italian subjects. Archives Gerontology and Geriatrics Supplement, 9, 339–348.

    CAS  Google Scholar 

  • Raz, N., Dahle, C. L., Rodrigue, K. M., Kennedy, K. M., Land, S. J., & Jacobs, B. S. (2008). Brain-derived neurotrophic factor Val66Met and blood glucose: a synergistic effect on memory. Frontiers in Human Neuroscience, 2, 12.

    PubMed  Google Scholar 

  • Raz, N., Rodrigue, K. M., Kennedy, K. M., & Land, S. (2009). Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension. Neuropsychology, 23, 105–116.

    PubMed  Google Scholar 

  • Reeves, S., Bench, C., & Howard, R. (2002). Aging and the nigrostriatal dopamine system. International Journal of Geriatric Psychiatry, 17, 359–370.

    CAS  PubMed  Google Scholar 

  • Rehman, H. U., & Masson, E. A. (2001). Neuroendocrinology of ageing. Age and Ageing, 30, 279–287.

    CAS  PubMed  Google Scholar 

  • Reynolds, C. A., Finkel, D., Gatz, M., & Pedersen, N. L. (2002). Sources of influence on rate of cognitive change over time in Swedish twins: an application of latent growth models. Experimental Aging Research, 28, 407–433.

    PubMed  Google Scholar 

  • Reynolds, C. A., Jansson, M., Gatz, M., & Pedersen, N. L. (2006). Longitudinal change in memory performance associated with HTR2A polymorphism. Neurobiology of Aging, 27, 150–154.

    CAS  PubMed  Google Scholar 

  • Ridley, M. (2003). Nature via nurture. New York: Harper Collins.

    Google Scholar 

  • Rinne, J. O., Lonnberg, P., & Marjamaki, P. (1990). Age-dependent decline of dopamine-D1 and dopamine-D2 receptor. Brain Research, 508, 349–352.

    CAS  PubMed  Google Scholar 

  • Rodgers, J. T., Lerin, C., Haas, W., Cygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434, 113–118.

    CAS  PubMed  Google Scholar 

  • Rodriguez-Murillo, L., & Greenberg, D. A. (2008). Genetic association analysis: a primer on how it works, its strengths and its weaknesses. International Journal of Andrology, 31, 546–556.

    PubMed  Google Scholar 

  • Rodríguez-Rodríguez, E., Infante, J., Llorca, J., Mateo, I., Sánchez-Quintana, C., García-Gorostiaga, I., et al. (2009). Age-dependent association of KIBRA genetic variation and Alzheimer’s disease risk. Neurobiology of Aging, 30, 322–324.

    PubMed  Google Scholar 

  • Ropers, H. H., & Hamel, B. C. (2005). X-linked mental retardation. Nature Reviews Genetics, 6, 46–57.

    CAS  PubMed  Google Scholar 

  • Roth, T. L., Lubin, F. D., Funk, A. J., & Sweatt, J. D. (2009). Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry, 65, 760–769.

    CAS  PubMed  Google Scholar 

  • Rujescu, D., Hartmann, A. M., Gonnermann, C., Möller, H. J., & Giegling, I. (2003). M129V variation in the prion protein may influence cognitive performance. Molecular Psychiatry, 8, 937–941.

    CAS  PubMed  Google Scholar 

  • Salthouse, T. A. (1996). The processing-speed theory of adult age differences in cognition. Psychological Review, 103, 403–428.

    CAS  PubMed  Google Scholar 

  • Sanderson, T. H., Kumar, R., Sullivan, J. M., & Krause, G. S. (2008). Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding. Journal of Neurochemistry, 106, 1248–1258.

    CAS  PubMed  Google Scholar 

  • Sarter, M., & Bruno, J. P. (2004). Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities. Neurobiology of Aging, 25, 1127–1139.

    CAS  PubMed  Google Scholar 

  • Savitz, J., Solms, M., & Ramesar, R. (2006). Apolipoprotein E variants and cognition in healthy individuals: a critical opinion. Brain Research Reviews, 51, 125–135.

    CAS  PubMed  Google Scholar 

  • Schaper, K., Kolsch, H., Popp, J., Wagner, M., & Jessen, F. (2008). KIBRA gene variants are associated with episodic memory in healthy elderly. Neurobiology of Aging, 29, 1123–1125.

    CAS  PubMed  Google Scholar 

  • Seshadri, S., DeStefano, A. L., Au, R., Massaro, J. M., Beiser, A. S., Kelly-Hayes, M., et al. (2007). Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Medical Genetics, 8, S15.

    PubMed  Google Scholar 

  • Sgaravatti, A. M., Sgarbi, M. B., Testa, C. G., Durigon, K., Pederzolli, C. D., Prestes, C. C., et al. (2007). Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats. Neurochemistry International, 50, 564–570.

    CAS  PubMed  Google Scholar 

  • Shenkin, S. D., Rivers, C. S., Deary, I. J., Starr, J. M., & Wardlaw, J. M. (2009). Maximum (prior) brain size, not atrophy, correlates with cognition in community-dwelling older people: a cross-sectional neuroimaging study. BMC Geriatric, 9, 12.

    Google Scholar 

  • Shepherd, C. E., Piguet, O., Broe, G. A., Creasey, H., Waite, L. M., Brooks, W. S., et al. (2004). Histocompatibility antigens, aspirin use and cognitive performance in non-demented elderly subjects. Journal of Neuroimmunology, 148, 178–182.

    CAS  PubMed  Google Scholar 

  • Shimokata, H., Ando, F., Niino, N., Miyasaka, K., & Funakoshi, A. (2005). Cholecystokinin A receptor gene promoter polymorphism and intelligence. Annals of Epidemiology, 15, 196–201.

    PubMed  Google Scholar 

  • Sild, M., Koca, C., Bendixen, M. H., Frederiksen, H., McGue, M., Kølvraa, S., et al. (2006). Possible associations between successful aging and polymorphic markers in the Werner gene region. Annals of the New York Academy of Sciences, 1067, 309–310.

    CAS  PubMed  Google Scholar 

  • Spearman, C. (1904). ‘General Intelligence’ objectively determined and measured. American Journal of Psychology, 15, 201–293.

    Google Scholar 

  • Starr, J. M., Fox, H., Harris, S. E., Deary, I. J., & Whalley, L. J. (2007). COMT genotype and cognitive ability: a longitudinal aging study. Neuroscience Letters, 421, 57–61.

    CAS  PubMed  Google Scholar 

  • Stefanis, N. C., Trikalinos, T. A., Avramopoulos, D., Smyrnis, N., Evdokimidis, I., Ntzani, E. E., et al. (2007). Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. Biological Psychiatry, 62, 784–792.

    CAS  PubMed  Google Scholar 

  • Sullivan, E. V., Pfefferbaum, A., Swan, G. E., & Carmelli, D. (2001). Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment. Hippocampus, 11, 754–762.

    CAS  PubMed  Google Scholar 

  • Tan, H. Y., Nicodemus, K. K., Chen, Q., Li, Z., Brooke, J. K., Honea, R., et al. (2008). Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. Journal of Clinical Investigation, 118, 2200–2208.

    CAS  PubMed  Google Scholar 

  • Tannenbaum, C., Mayo, N., & Ducharme, F. (2005). Older women's health priorities and perceptions of care delivery: results of the WOW health survey. Canadian Medical Association Journal, 173, 153–159.

    PubMed  Google Scholar 

  • Thompson, R. F., & Kim, J. J. (1996). Memory systems in the brain and localization of a memory. Proceedings of the National Academy of Sciences of the United States of America, 93, 13438–13444.

    CAS  PubMed  Google Scholar 

  • Thomson, P. A., Harris, S. E., Starr, J. M., Whalley, L. J., Porteous, D. J., & Deary, I. J. (2005). Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neuroscience Letters, 389, 41–45.

    CAS  PubMed  Google Scholar 

  • Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., et al. (2008). A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature, 452, 638–642.

    CAS  PubMed  Google Scholar 

  • Togsverd, M., Werge, T. M., Tankó, L. B., Bagger, Y. Z., Qin, G. G., Hansen, T., et al. (2007). Cognitive performance in elderly women: significance of the 19 bp insertion/deletion polymorphism in the 5' flank of the dopamine beta-hydroxylase gene, educational level, body fat measures, serum triglyceride, alcohol consumption and age. International Journal of Geriatric Psychiatry, 22, 883–889.

    PubMed  Google Scholar 

  • Tombaugh, T. N., & McIntyre, N. J. (1992). The mini-mental state examination: a comprehensive review. Journal of the American Geriatrics Society, 40, 922–935.

    CAS  PubMed  Google Scholar 

  • Tsai, S. J., Yu, Y. W., Lin, C. H., Chen, T. J., Chen, S. P., & Hong, C. J. (2002). Dopamine D2 receptor and N-methyl-D-aspartate receptor 2B subunit genetic variants and intelligence. Neuropsychobiology, 45, 128–130.

    CAS  PubMed  Google Scholar 

  • Tsai, S. J., Gau, Y. T., Liu, M. E., Hsieh, C. H., Liou, Y. J., & Hong, C. J. (2008). Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia. Neuroscience Letters, 433, 158–162.

    CAS  PubMed  Google Scholar 

  • van den Berg, E., Kloppenborg, R. P., Kessels, R. P., Kappelle, L. J., & Biessels, G. J. (2009). Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition. Biochimica et Biophysica Acta, 1792, 470–481.

    PubMed  Google Scholar 

  • van Kesteren, R. E., & Spencer, G. E. (2003). The role of neurotransmitters in neurite outgrowth and synapse formation. Reviews in the Neurosciences, 14, 217–231.

    PubMed  Google Scholar 

  • Versijpt, J., Van Laere, K. J., Dumont, F., Decoo, D., Vandecapelle, M., Santens, P., et al. (2003). Imaging of the 5-HT2A system: age-, gender-, and Alzheimer's disease-related findings. Neurobiology of Aging, 24, 553–561.

    CAS  PubMed  Google Scholar 

  • Visscher, P. M., Tynan, M., Whiteman, M. C., Pattie, A., White, I., Hayward, C., et al. (2003). Lack of association between polymorphisms in angiotensin-converting-enzyme and methylenetetrahydrofolate reductase genes and normal cognitive ageing in humans. Neuroscience Letters, 347, 175–178.

    CAS  PubMed  Google Scholar 

  • Volkow, N. D., Gur, R. C., Wang, G. J., Fowler, J. S., Moberg, P. J., Ding, Y. S., et al. (1998). Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. American Journal of Psychiatry, 155, 344–349.

    CAS  PubMed  Google Scholar 

  • Wacholder, S., Rothman, N., & Caporaso, N. (2002). Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiology Biomarkers Prevention, 11, 513–520.

    Google Scholar 

  • Wang, H., Yuan, G., Prabhakar, N. R., Boswell, M., & Katz, D. M. (2006). Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling. Journal of Neurochemistry, 96, 694–705.

    CAS  PubMed  Google Scholar 

  • Wang, F. T., Hu, H., Schwartz, J., Weuve, J., Spiro, A. S., Sparrow, D., et al. (2007). Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline. Environmental Health Perspectives, 115, 1210–1215.

    Article  CAS  PubMed  Google Scholar 

  • Webster, M. J., Weickert, C. S., Herman, M., & Kleinman, J. E. (2002). BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Developmental Brain Research, 139, 139–150.

    CAS  PubMed  Google Scholar 

  • West, M. J., Coleman, P. D., Flood, D. G., & Troncoso, J. C. (1994). Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet, 344, 769–772.

    CAS  PubMed  Google Scholar 

  • Whitmer, R. A., Gunderson, E. P., Quesenberry, C. P., Jr., Zhou, J., & Yaffe, K. (2007). Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Current Alzheimer Research, 4, 103–109.

    CAS  PubMed  Google Scholar 

  • Wisdom, N. M., Callahan, J. L., & Hawkins, K. A. (2009). The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiol Aging, (in press) PMID: 19285755.

  • Yaffe, K., Kanaya, A. M., Lindquist, K., Hsueh, W. C., Cummings, S. R., Beamer, B., et al. (2008). Health ABC Study. PPAR-gamma Pro12Ala genotype and risk of cognitive decline in elders. Neurobiology of Aging, 29(1), 78–83.

    CAS  PubMed  Google Scholar 

  • Yaffe, K., Lindquist, K., Sen, S., Cauley, J., Ferrell, R., Penninx, B., et al. (2009). Estrogen receptor genotype and risk of cognitive impairment in elders: Findings from the Health ABC study. Neurobiology of Aging, 30, 607–614.

    CAS  PubMed  Google Scholar 

  • Yang, B. Z., Kranzler, H. R., Zhao, H., Gruen, J. R., Luo, X., & Gelernter, J. (2008). Haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 are associated with comorbid alcohol and drug dependence. Alcoholism, Clinical and Experimental Research, 32, 2117–2127.

    CAS  PubMed  Google Scholar 

  • Yu, Y. W., Tsai, S. J., Hong, C. J., Chen, M. C., Yang, C. W., & Chen, T. J. (2005). Association study of a functional MAOA-uVNTR gene polymorphism and cognitive function in healthy females. Neuropsychobiology, 52, 77–82.

    CAS  PubMed  Google Scholar 

  • Zinkstok, J. R., de Wilde, O., van Amelsvoort, T. A., Tanck, M. W., Baas, F., & Linszen, D. H. (2007). Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings. Behavioral and Brain Functions, 3, 19.

    PubMed  Google Scholar 

Download references

Disclosures

I have no conflicts of interest to report.

Author information

Authors and Affiliations

  1. Centre for Integrated Genomic Medical Research, University of Manchester, Stopford Building, Oxford road, Manchester, M13 9PT, UK

    Antony Payton

Authors
  1. Antony Payton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antony Payton.

Genetic glossary

Allele

One of a number of different polymorphic states. For example for an SNP where a T is replaced by a G, the T and G are the two alleles

Epigenetic

Describes something which influences the behaviour of a cell without directly affecting its DNA or other genetic machinery, such as an environmental effect

Exon

Coding regions of DNA that are transcribed and translated into protein

Genotype

The specific allele makeup of a polymorphism. For example, an SNP where an A is the common allele and a T is the minor allele can have three potential genotypes: homozygous AA or TT, or heterozygous AT

Haplotype

A set of polymorphisms from the same region which are usually inherited as a unit

Heterozygous

Occurs when alleles at the same chromosomal position are different. For example if a T is inherited from a specific genetic location from the mother and an A is inherited at the same position from the father then the genotype will be heterozygous (AT)

Homozygous

Occurs when alleles at the same chromosomal position are the same

Intron

Regions of DNA located between exons which do not translate into protein

Mutation

DNA variations that occur at a frequency of less than 1% within a population

Non-synonymous

A substitution of one nucleotide for another nucleotide within an exon of a gene that results in the production of a different amino acid

Polymorphism

DNA variations that occur at a frequency of greater than 1% within a population

Promoter site

Region of DNA that regulates the amount of protein produced

Single nucleotide polymorphism (SNP)

DNA sequence variation occurring at a single nucleotide. They are identified by an individual reference sequence (rs) number. For example rs6265 (an SNP within the BDNF gene)

Stochastic

Random or probabilistic event

TagSNP

Multiple SNPs can be inherited together on a single block of DNA (these SNPs are said to be in linkage disequilibrium). Therefore, it is possible to genotype a small number of SNPs on a block in order to identify a haplotype. The selected SNPs are called tagSNPs and they are a way of reducing genotyping costs while maintaining power to detect association.

Transcription

Transfer of genetic information from DNA to RNA

Rights and permissions

Reprints and permissions

About this article

Cite this article

Payton, A. The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009. Neuropsychol Rev 19, 451–477 (2009). https://doi.org/10.1007/s11065-009-9116-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11065-009-9116-z

Keywords

Search

Navigation