Behavior Genetics

, Volume 49, Issue 5, pp 455–468 | Cite as

Cognitive Performance in Young APOE ε4 Carriers: A Latent Variable Approach for Assessing the Genotype–Phenotype Relationship

  • Xiaojing Li
  • Andrea HildebrandtEmail author
  • Werner Sommer
  • Oliver Wilhelm
  • Martin Reuter
  • Christian Montag
  • Changsong ZhouEmail author
Original Research


The ε4 allele of the apolipoprotein (APOE) gene is a widely recognized genetic risk factor for developing Alzheimer’s disease in older age. However, it is controversial whether there is a positive impact of the APOE ε4 allele on human cognitive performance in young adulthood, possibly representing a case of antagonistic pleiotropy. Here we explored associations of the APOE ε4 allele with cognitive ability in young adulthood. In contrast to previous studies, we used structural equation modeling that allows a multivariate measurement of the cognitive phenotype. Results based on four independent samples (N1 = 245; N2 = 300; N3 = 244; N4 = 206) overall revealed a complex effect of the APOE ε4 genotype on cognitive ability in young adulthood: Whereas the ε4 allele tends to be negatively associated with cognitive performance in individuals with lower education levels, there might be a weak positive association in persons with higher education—a finding that is partly in line with the antagonistic pleiotropy view on APOE and cognitive ability. The education-related findings support protective effects of environmental factors.


Working memory Secondary memory Reasoning APOE Structural equation modeling 



This research was supported by a scholarship awarded from Hong Kong Baptist University and an Elsa-Neumann-Scholarship from Humboldt Universität zu Berlin to Xiaojing Li. The study was also supported by a Research Group Linkage Project funded by the Alexander von Humboldt Foundation to Andrea Hildebrandt, Werner Sommer and Changsong Zhou. Behavioral data collection was funded by a grant of the Deutsche Forschungsgemeinschaft (HI 1780/2-1 & SO 177/26-1) awarded to Andrea Hildebrandt and Werner Sommer. Genetic analysis was supported by the Hong Kong Baptist University (HKBU) Strategic Development Fund and the Hong Kong Baptist University Research Committee Interdisciplinary Research Matching Scheme (IRMS/16-17/04) awarded to Changsong Zhou. The position of Christian Montag is funded by a Heisenberg grant awarded to him by the German Research Foundation (DFG, MO2363/3-2).

Compliance with ethical standards

Conflict of interest

Xiaojing Li, Andrea Hildebrandt, Werner Sommer, Oliver Wilhelm, Martin Reuter, Christian Montag, and Changsong Zhou declare that they have no conflict of interest.

Ethical approval

All data collections had been approved by the ethics committee of Humboldt-Universität zu Berlin (Ref.-nr. 2013-01) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was collected for all participants involved in the studies.

Supplementary material

10519_2019_9961_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)
10519_2019_9961_MOESM2_ESM.txt (72 kb)
Supplementary material 2 (TXT 71 kb)
10519_2019_9961_MOESM3_ESM.csv (31 kb)
Supplementary material 3 (CSV 31 kb)
10519_2019_9961_MOESM4_ESM.txt (16 kb)
Supplementary material 4 (TXT 15 kb)
10519_2019_9961_MOESM5_ESM.txt (15 kb)
Supplementary material 5 (TXT 14 kb)


  1. Alexander DM, Williams LM, Gatt JM et al (2007) The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biol Psychol 75:229–238CrossRefGoogle Scholar
  2. Alexopoulos P, Richter-schmidinger T, Horn M et al (2011) Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers. J Alzheimers Dis. 26:207–210CrossRefGoogle Scholar
  3. Allison PD (2001) Missing Data. In: Millsap RE, Maydeu-Olivares A (eds) The SAGE handbook of quantitative methods in psychology. SAGE, London, pp 73–90Google Scholar
  4. Arenaza-Urquijo EM, Landeau B, La Joie R et al (2013) Relationships between years of education and gray matter volume, metabolism and functional connectivity in healthy elders. Neuroimage 83:450–457CrossRefGoogle Scholar
  5. Arenaza-Urquijo EM, Gonneaud J, Fouquet M et al. (2015). Interaction between years of education and APOE ε4 status on frontal and temporal metabolism. Neurology 85:1392–1399CrossRefGoogle Scholar
  6. Baddeley A, Hitch G (1974) Working memory. Psychol Learn Motiv 8:47–89CrossRefGoogle Scholar
  7. Bloss CS, Delis DC, Salmon DP et al (2008) Decreased cognition in children with risk factors for Alzheimer’s Disease. Biol Psychiatry 64:904–906CrossRefGoogle Scholar
  8. Craik F, Byrd M (1982) Aging and cognitive deficits: the role of attentional resources. In: Craik FIM, Trehub S (eds) Aging and cognitive processes. Plenum, New York, pp 199–211CrossRefGoogle Scholar
  9. Dennis NA, Browndyke JN, Stokes J et al (2010) Temperal lobe functional activity and connectivity in young adult APOE e4 carriers. Alzheimers Dement 6:303–311CrossRefGoogle Scholar
  10. Dong Y, Peng CYJ (2013) Principled missing data methods for researchers. SpringerPlus 2:222CrossRefGoogle Scholar
  11. Dowell NG, Ruest T, Evans SL et al (2013) MRI of carriers of the apolipoprotein E e4 allele-evidence for structural differences in normal-appearing brain tissue in e4+ relative to e4− young adults. NMR Biomed 26:674–682PubMedGoogle Scholar
  12. Engle RW, Tuholski SW, Laughlin JE (1999) Working memory, short-term memory, and general fluid intelligence: a latent-variable approach. J Exp Psychol Gen 128:309–331CrossRefGoogle Scholar
  13. Eramudugolla R, Bielak AAM, Bunce D et al (2014) Long-term cognitive correlates of traumatic brain injury across adulthood and interactions with APOE genotype, sex, and age cohorts. J Int Neuropsychol Soc 20:444–454CrossRefGoogle Scholar
  14. Estévez-González A, García-Sánchez C, Boltes A et al (2004) Preclinical memory profile in Alzheimer patients with and without allele APOE-epsilon4. Eur Neurol 51:199–205CrossRefGoogle Scholar
  15. Evans S, Gray MA, Dowell NG et al (2013) APOE E4 Carriers show prospective memory enhancement under nicotine, and evidence for specialisation within medial BA10. Neuropsychopharmacology 38:655–663CrossRefGoogle Scholar
  16. Fouquet M, Besson FL, Gonneaud J et al (2014) Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. Neuropsychol Rev 24:290–299CrossRefGoogle Scholar
  17. Greenwood PM, Lambert C, Sunderland T et al (2005) Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: results From the National Institute of Mental Health’s BIOCARD study. Neuropsychology 19:199–211CrossRefGoogle Scholar
  18. Han SD, Bondi MW (2008) Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimers Dement. 4:251–254CrossRefGoogle Scholar
  19. Hildebrandt A, Kiy A, Reuter M et al (2016) Face and emotion expression processing and the serotonin transporter polymorphism 5-HTTLPR/rs22531. Genes Brain Behav 15:453–464CrossRefGoogle Scholar
  20. Hu LT, Bentler PM (1995) Evaluating Model Fit. In: Hoyle RH (ed) Structural equation modeling: concepts, issues, and applications. SAGE, US, pp 76–99Google Scholar
  21. Hubacek JA, Pitha J, Skodova Z et al (2001) A possible role of apolipoprotein E polymorphism in predisposition to higher education. Neuropsychobiology 43:200–203CrossRefGoogle Scholar
  22. Ihle A, Bunce D, Kliegel M (2012) APOE ε4 and cognitive function in early life: a meta-analysis. Neuropsychology 26:267–277CrossRefGoogle Scholar
  23. Izaks GJ, Gansevoort RT, Knaap AM (2011) The association of APOE genotype with cognitive function in persons aged 35 years or older. PLoS ONE 6:1–8Google Scholar
  24. Kane MJ, Hambrick DZ, Tuholski SW et al (2004) The domain generality of working- memory capacity: a latent-variable approach to verbal and spatial memory span and reasoning. J Exp Psychol 133:189–217CrossRefGoogle Scholar
  25. Kunz L, Schroeder TN, Lee H et al (2015) Reduced grid-like representations in adults at genetic risk for Alzheimer’s disease. Science 350:430–433CrossRefGoogle Scholar
  26. Kyllonen PC, Christal RE (1990) Reasoning ability is (little more than) working memory capacity?! Intelligence 14:389–433CrossRefGoogle Scholar
  27. Marioni RE, Campbell A, Scotland G et al (2016) Differential effects of the APOE e4 allele on different domains of cognitive ability across the life-course. Eur J Hum Genet 24:919–923CrossRefGoogle Scholar
  28. Matura S, Prvulovic D, Jurcoane A et al (2014) Differential effects of the ApoE4 genotype on brain structure and function. NeuroImage 89:81–91CrossRefGoogle Scholar
  29. Merchant NL, King SL, Tabet N et al (2010) Positive effects of cholinergic stimulation favor young APOE ε4 carriers. Neuropsychopharmacology 35:1090–1096CrossRefGoogle Scholar
  30. Mondadori CRA, Quervain DJF, Buchmann A et al (2007) Better memory and neural efficiency in young Apolipoprotein E4 carriers. Cereb Cortex 17:1934–1947CrossRefGoogle Scholar
  31. Oberauer K, Süß HM, Schulze R (2000) Working memory capacity—facets of a cognitive ability construct. Pers Individ Differ 29:1017–1045CrossRefGoogle Scholar
  32. Oberauer K, Schulze R, Wilhelm O et al (2005) Working memory and intelligence—their correlation and their relation: comment on Ackerman, Beier, and Boyle. Psychol Bull 131:61–65CrossRefGoogle Scholar
  33. Oberauer K, Süß HM, Wilhelm O et al (2007) Individual differences in working memory capacity and reasoning ability. In: Conway A, Jarrold C, Kane M et al (eds) Variation in working memory. Oxford University Press, Oxford, pp 49–75Google Scholar
  34. Oriá RB, Patrick PD, Zhang H et al (2005) APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil. Pediatr Res 57:310–316CrossRefGoogle Scholar
  35. Puttonen S, Elovainio M, Kivimäki M et al (2003) The combined effects of Apolipoprotein E polymorphism and low-density lipoprotein cholesterol on cognitive performance in young adults. Neuropsychobiology 48:35–40CrossRefGoogle Scholar
  36. Raven JC, Court JH (1979) Manual for Raven's progressive matrices and vocabulary scales. Harcourt Assessment, San Antonio, TXGoogle Scholar
  37. Reinvang I, Winjevoll IL, Rootwelt H et al (2010) Working memory deficits in healthy APOE epsilon 4 carriers. Neuropsychologia 48:566–573CrossRefGoogle Scholar
  38. Rusted J, Carare RO (2015) Are the effects of APOE ϵ4 on cognitive function in nonclinical populations age- and gender-dependent? Neurodegener Dis Manag 5:37–48CrossRefGoogle Scholar
  39. Rusted JM, Evans SL, King SL et al (2013) APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. NeuroImage 65:364–373CrossRefGoogle Scholar
  40. Schafer JL (1997) Analysis of incomplete multivariate data. Chapman and Hall, LondonCrossRefGoogle Scholar
  41. Schmiedek F, Hildebrandt A, Lövdén M et al (2009) Complex span versus updating tasks of working memory: the gap is not that deep. J Exp Psychol Learn Mem Cogn 35:1089–1096CrossRefGoogle Scholar
  42. Schmiedek F, Lövdén M, Lindenberger U (2014) A task is a task: putting complex span, n-back, and other working memory indicators in psychometric context. Front Psychol 5:1475CrossRefGoogle Scholar
  43. Shipstead Z, Lindsey DRB, Marshall RL et al (2014) The mechanisms of working memory capacity: primary memory, secondary memory, and attention control. J Mem Lang 72:116–141CrossRefGoogle Scholar
  44. Sinclair LI, Button KS, Munafò MR et al (2015) Possible association of APOE genotype with working memory in young adults. PLoS ONE 10:1–13Google Scholar
  45. Small BJ, Rosnick CB, Fratiglioni L et al (2004) Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 19:592–600CrossRefGoogle Scholar
  46. Süß HM, Oberauer K, Wittmann WW et al (2002) Working-memory capacity explains reasoning ability—and a little bit more. Intelligence 30:261–288CrossRefGoogle Scholar
  47. Tukey JW (1977) Exploratory data analysis, 1st edn. Addison-Wesley, ReadingGoogle Scholar
  48. Unsworth N, Spillers GJ (2010) Working memory capacity: attention control, secondary memory, or both? A direct test of the dual-component model. J Mem Lang 62:392–406CrossRefGoogle Scholar
  49. Unsworth N, Fukuda K, Awh E et al (2014) Working memory and fluid intelligence: capacity, attention control, and secondary memory retrieval. Cogn Psychol 71:1–26CrossRefGoogle Scholar
  50. Valenzuela MJ, Sachdev P (2006) Brain reserve and dementia: a systematic review. Psychol Med 36:441–454CrossRefGoogle Scholar
  51. Velichkovsky BB, Roschina IF, Selezneva ND (2015) Cognitive control and memory in healthy ApoE-E4 carriers with a family history of Alzheimer’s disease. Psychol Russia 8:4–13Google Scholar
  52. Wacker J, Mueller EM, Stemmler G (2012) How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research. J Pers Soc Psychol 102:427–444CrossRefGoogle Scholar
  53. Weissberger GH, Nation DA, Nguyen CP et al (2018) Meta-Analysis of Cognitive Ability Differences by Apolipoprotein E Genotype in Young Humans. Neurosci Biobehav Rev 94:49–58CrossRefGoogle Scholar
  54. Wilhelm O, Hildebrandt A, Oberauer K (2013) What is working memory capacity, and how can we measure it? Front Psychol 4:433CrossRefGoogle Scholar
  55. Wisdom NM, Callahan JL, Hawkins KA (2011) The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis. Neurobiol Aging 32:63–74CrossRefGoogle Scholar
  56. Wolk DA, Dickerson BC, ADNI (2010) Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease. Proc Natl Acad Sci USA 107:10256–10261CrossRefGoogle Scholar
  57. Woo M, Kim Y (2017) Cortical functional connections and fluid intelligence in adolescent APOE ε4 carriers. Dement Geriatr Cogn Disord 44:153–159CrossRefGoogle Scholar
  58. Yu YW, Lin CH, Chen SP et al (2000) Intelligence and event-related potentials for young female human volunteer apolipoprotein E epsilon4 and non-epsilon4 carriers. Neurosci Lett 294:179–181CrossRefGoogle Scholar
  59. Zokaei N, Čepukaitytė G, Board AG et al (2019) Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories. Neurobiol Aging 73:115–122CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Xiaojing Li
    • 1
    • 2
  • Andrea Hildebrandt
    • 3
    Email author
  • Werner Sommer
    • 2
  • Oliver Wilhelm
    • 4
  • Martin Reuter
    • 5
    • 6
  • Christian Montag
    • 4
    • 7
  • Changsong Zhou
    • 1
    Email author
  1. 1.Department of Physics, Centre for Nonlinear Studies, Institute of Computational and Theoretical StudiesHong Kong Baptist UniversityKowloon TongHong Kong
  2. 2.Department of PsychologyHumboldt-Universität zu BerlinBerlinGermany
  3. 3.Department of PsychologyCarl von Ossietzky Universität OldenburgOldenburgGermany
  4. 4.Department of PsychologyUlm UniversityUlmGermany
  5. 5.Centre for Economics and NeuroscienceUniversity of BonnBonnGermany
  6. 6.Department of PsychologyUniversity of BonnBonnGermany
  7. 7.The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for NeuroinformationUniversity of Electronic Science and Technology of ChinaChengduChina

Personalised recommendations