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The Elusive Nature of APOE ε4 in Mid-adulthood: Understanding the Cognitive Profile

Published online by Cambridge University Press:  06 January 2017

Claire Lancaster ,
Naji Tabet  and
Jennifer Rusted
Claire Lancaster
Affiliation:
School of Psychology, University of Sussex, Brighton, East Sussex
Naji Tabet
Affiliation:
Brighton and Sussex Medical School, Institute of Postgraduate Medicine, Brighton, East Sussex
Jennifer Rusted*
Affiliation:
School of Psychology, University of Sussex, Brighton, East Sussex
*
Correspondence and reprint requests to: Jennifer Rusted, School of Psychology, University of Sussex, Brighton, East Sussex, BN1 9QG. E-mail: j.rusted@sussex.ac.uk
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Abstract

Objectives: The apolipoprotein E (APOE) ε4 allele is an established risk factor for dementia, yet this genetic variant is associated with a mixed cognitive profile across the lifespan. This study undertakes both a systematic and meta-analytic review of research investigating APOE-related differences in cognition in mid-adulthood, when detrimental effects of the allele may first be detectable. Methods: Thirty-six papers investigating the behavioral effects of APOE ε4 in mid-adulthood (defined as a mean sample age between 35 and 60 years) were reviewed. In addition, the effect of carrying an ε4 allele on individual cognitive domains was assessed in separate meta-analyses. Results: The average effect size of APOE ε4 status was non-significant across cognitive domains. Further consideration of genotype effects indicates preclinical effects of APOE ε4 may be observable in memory and executive functioning. Conclusions: The cognitive profile of APOE ε4 carriers at mid-age remains elusive. Although there is support for comparable performance by ε4 and non-e4 carriers in the 5th decade, studies administering sensitive cognitive paradigms indicate a more nuanced profile of cognitive differences. Methodological issues in this field preclude strong conclusions, which future research must address, as well as considering the influence of further vulnerability factors on genotype effects. (JINS, 2016, 23, 239–253)

Keywords

Cognitive agingMiddle-agedNeuroimagingAlzheimer diseaseMemoryExecutive function
Type
Critical Reviews
Information
Journal of the International Neuropsychological Society , Volume 23 , Issue 3 , March 2017 , pp. 239 - 253
Copyright
Copyright © The International Neuropsychological Society 2016 

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References

REFERENCES

Alexander, D.M., Williams, L.M., Gatt, J.M., Dobson-Stone, C., Kuan, S.A., Todd, E.G., & Gordon, E. (2007). The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biological Psychology, 75(3), 229–238. doi: 10.1016/j.biopsycho.2007.03.001 CrossRefGoogle ScholarPubMed
Alzheimer’s Society. (2016). Alzheimersorguk. Retrieved 5 April, 2016, from https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=341.Google Scholar
Atzmon, G., Gabriely, I., Greiner, W., Davidson, D., Schechter, C., & Barzilai, N. (2002). Plasma HDL levels highly correlate with cognitive function in exceptional longevity. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 57(11), 712–715. doi: 10.1093/gerona/57.11.M712 Google Scholar
Bender, A.R., & Raz, N. (2012). Age-related differences in memory and executive functions in healthy APOE ɛ4 carriers: The contribution of individual differences in prefrontal volumes and systolic blood pressure. Neuropsychologia, 50(5), 704–714. doi: 10.1016/j.neuropsychologia.2011.12.025 Google Scholar
Blair, C.K., Folsom, A.R., Knopman, D.S., Bray, M.S., Mosley, T.H., & Boerwinkle, E. (2005). APOE genotype and cognitive decline in a middle-aged cohort. Neurology, 64(2), 268–276. doi: 10.1212/01.WNL.0000149643.91367.8A Google Scholar
Borenstein, M., Hedges, L., Higgins, J., & Rothstein, H. (2009). Complex data structures, Introduction to meta-analysis (pp. 215–245). West Sussex, UK: John Wiley & Sons Ltd.CrossRefGoogle Scholar
Bunce, D., Anstey, K.J., Burns, R., Christensen, H., & Easteal, S. (2011). Does possession of apolipoprotein E ɛ4 benefit cognitive function in healthy young adults? Neuropsychologia, 49(7), 1693–1697. doi: 10.1016/j.neuropsychologia.2011.02.042 Google Scholar
Bunce, D., Bielak, A.A.M., Anstey, K.J., Cherbuin, N., Batterham, P.J., & Easteal, S. (2014). APOE genotype and cognitive change in young, middle-aged, and older adults living in the community. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 69(4), 379–386. doi: 10.1093/gerona/glt103 Google Scholar
Bunce, D., Kivipelto, M., & Wahlin, A. (2004). Utilization of cognitive support in episodic free recall as a function of apolipoprotein E and vitamin B12 or folate among adults aged 75 years and older. Neuropsychology, 18(2), 362–370. doi: 10.1037/0894-4105.18.2.362 Google Scholar
Caselli, R.J., Chen, K., Lee, W., Alexander, G.E., & Reiman, E.M. (2008). Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre–mild cognitive impairment. Archives of Neurology, 65(9), 1231–1236.Google Scholar
Caselli, R.J., Chen, K., Locke, D.E.C., Lee, W., Roontiva, A., Bandy, D., & Reiman, E.M. (2014). Subjective cognitive decline: Self and informant comparisons. Alzheimer’s & Dementia, 10(1), 93–98.Google Scholar
Caselli, R.J., Dueck, A.C., Locke, D.E.C., Hoffman-Snyder, C.R., Woodruff, B.K., Rapcsak, S.Z., & Reiman, E.M. (2011). Longitudinal modeling of frontal cognition in APOE ϵ4 homozygotes, heterozygotes, and noncarriers. Neurology, 76(16), 1383–1388. doi: 10.1212/WNL.0b013e3182167147 Google Scholar
Caselli, R.J., Dueck, A.C., Osborne, D., Sabbagh, M.N., Connor, D.J., Ahern, G.L., & Reiman, E.M. (2009). Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. The New England Journal of Medicine, 361, 255–263. doi: 10.1016/S0084-3954(09)79603-4 Google Scholar
Caselli, R.J., Graff–Radford, N.R., Reiman, E.M., Weaver, A., Osborne, D., Lucas, J., & Thibodeau, S.N. (1999). Preclinical memory decline in cognitively normal apolipoprotein E–ε4 homozygotes. Neurology, 53(1), 201.Google Scholar
Chen, C.-J., Chen, C.-C., Wu, D., Chi, N.-F., Chen, P.-C., Liao, Y.-P., & Hu, C.-J. (2013). Effects of the apolipoprotein E ε4 allele on functional MRI during n-back working memory tasks in healthy middle-aged adults. AJNR American Journal of Neuroradiology, 34(6), 1197–1202. doi: 10.3174/ajnr.A3369 Google Scholar
Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G., & Pericak-Vance, M. (1993). Gene does of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921–923.CrossRefGoogle ScholarPubMed
DeCoster, J. (2009). Meta-analysis notes. Retrieved 07/28/2016 from http://www.stat-help.com/notes.html.Google Scholar
Deeny, S.P., Poeppel, D., Zimmerman, J.B., Roth, S.M., Brandauer, J., Witkowski, S., & Brandt, J. (2008). Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers. Biological Psychology, 78(2), 179–187.Google Scholar
Donix, M., Burggren, A.C., Suthana, N.A., Siddarth, P., Ekstrom, A.D., Krupa, A.K., & Bookheimer, S.Y. (2010). Family history of Alzheimer’s disease and hippocampal structure in healthy people. American Journal of Psychiatry, 167(11), 1399–1406. doi: 10.1176/appi.ajp.2010.09111575 Google Scholar
Evans, S., Dowell, N.G., Tabet, N., Tofts, P.S., King, S.L., Gray, M., & Rusted, J.M. (2013). Nicotine effects on attentional reorienting in mid-age adults, and interactions with apolipoprotein E status. Journal of Psychopharmacology (Oxford, England), 27(11), 1007–1014. doi: 10.1177/0269881113499828 CrossRefGoogle ScholarPubMed
Evans, S., Dowell, N.G., Tabet, N., Tofts, P.S., King, S.L., & Rusted, J.M. (2014). Cognitive and neural signatures of the APOE Ε4 allele in mid-aged adults. Neurobiology of Aging, 35(7), 1615–1623. doi: 10.1016/j.neurobiolaging.2014.01.145 Google Scholar
Farrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., & van Duijn, C.M. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 278(16), 1349–1356. doi: 10.1001/jama.1997.03550160069041 Google Scholar
Flory, J.D., Manuck, S.B., Ferrell, R.E., Ryan, C.M., & Muldoon, M.F. (2000). Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. American Journal of Medical Genetics, 96(6), 707–711. doi: 10.1002/1096-8628(20001204)96:6<707::AID-AJMG1>3.0.CO;2-V Google Scholar
De Frias, C.M., Schaie, K.W., & Willis, S.L. (2014). Hypertension moderates the effect of APOE on 21-year cognitive trajectories. Psychology and Aging, 29(2), 431–439. doi: 10.1037/a0036828 CrossRefGoogle ScholarPubMed
Goveas, J.S., Xie, C., Chen, G., Li, W., Ward, B.D., Franczak, M.B., & Li, S.-J. (2013). Functional network endophenotypes unravel the effects of apolipoprotein E epsilon 4 in middle-aged adults. PloS One, 8(2), e55902. doi: 10.1371/journal.pone.0055902 CrossRefGoogle ScholarPubMed
Greenwood, P.M., Sunderland, T., Friz, J.L., & Parasuraman, R. (2000). Genetics and visual attention: Selective deficits in healthy adult carriers of the ɛ4 allele of the apolipoprotein E gene. Proceedings of the National Academy of Sciences of the United States of America, 97(21), 11661–11666.Google Scholar
Greenwood, P.M., Lambert, C., Sunderland, T., & Parasuraman, R. (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(2), 199–211.Google Scholar
Greenwood, P.M., Espeseth, T., Lin, M.-K., Reinvang, I., & Parasuraman, R. (2014). Longitudinal change in working memory as a function of APOE genotype in midlife and old age. Scandinavian Journal of Psychology, 55(3), 268–277. doi: 10.1111/sjop.12123 CrossRefGoogle ScholarPubMed
Greenwood, P.M., Sunderland, T., Putnam, K., Levy, J., & Parasuraman, R. (2005). Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age: Results from the NIMH BIOCARD Study. Neuropsychology, 19(6), 830–840. doi: 10.1037/0894-4105.19.6.830 Google Scholar
Han, S.D., & Bondi, M.W. (2008). Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimer’s & Dementia, 4(4), 251–254. doi: 10.1016/j.jalz.2008.02.006 CrossRefGoogle ScholarPubMed
Han, S.D., Drake, A.I., Cessante, L.M., Jak, A.J., Houston, W.S., Delis, D.C., & Bondi, M.W. (2007). Apolipoprotein E and traumatic brain injury in a military population: Evidence of a neuropsychological compensatory mechanism? Journal of Neurology, Neurosurgery, and Psychiatry, 78(10), 1103–1108. doi: 10.1136/jnnp.2006.108183 Google Scholar
Herrup, K. (2010). Reimagining Alzheimer’s disease--An age-based hypothesis. Journal of Neuroscience, 30(50), 16755–16762. doi: 10.1523/JNEUROSCI.4521-10.2010 Google Scholar
Hubacek, J.A., Pitha, J., Škodová, Z., Adámková, V., Lánská, V., & Poledne, R. (2001). A possible role of apolipoprotein E polymorphism in predisposition to higher education. Neuropsychobiology, 43(3), 200–203. doi: 10.1159/000054890 Google Scholar
Ihle, A., Bunce, D., & Kliegel, M. (2012). APOE ε4 and cognitive function in early life: A meta-analysis. Neuropsychology, 26(3), 267–277. doi: 10.1037/a0026769 Google Scholar
Jochemsen, H.M., Muller, M., van der Graaf, Y., & Geerlings, M.I. (2012). APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiology of Aging, 33(4), 832.e15–e22. doi: 10.1016/j.neurobiolaging.2011.07.016 Google Scholar
Jorm, A.F., Mather, K.A., Butterworth, P., Anstey, K.J., Christensen, H., & Easteal, S. (2007). APOE genotype and cognitive functioning in a large age-stratified population sample. Neuropsychology, 21(1), 1–8. doi: 10.1037/0894-4105.21.1.1 Google Scholar
Köhler, S., Baars, M.A.E., Spauwen, P., Schievink, S., Verhey, F.R.J., & van Boxtel, M.J.P. (2014). Temporal evolution of cognitive changes in incident hypertension: Prospective cohort study across the adult age span. Hypertension, 63(2), 245–251. doi: 10.1161/HYPERTENSIONAHA.113.02096 Google Scholar
Kozauer, N.A., Mielke, M.M., Chan, G.K.C., Rebok, G.W., & Lyketsos, C.G. (2008). Apolipoprotein E genotype and lifetime cognitive decline. International Psychogeriatrics, 20(01), 109–123. doi: 10.1017/S104161020700587X Google Scholar
Langbaum, J.B.S., Chen, K., Caselli, R.J., Lee, W., Reschke, C., Bandy, D., & Reeder, S.A. (2010). Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E ε4 allele. Archives of Neurology, 67(4), 462–468.Google Scholar
Levy, J.A., Bergeson, J., Putnam, K., Rosen, V., Cohen, R., Lalonde, F., & Sunderland, T. (2004). Context-specific memory and apolipoprotein E (ApoE) epsilon 4: Cognitive evidence from the NIMH prospective study of risk for Alzheimer’s disease. Journal of the International Neuropsychological Society, 10(3), 362–370. doi: 10.1017/S1355617704103044 Google Scholar
Li, W., Antuono, P.G., Xie, C., Chen, G., Jones, J.L., Ward, B.D., & Li, S.-J. (2014). Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOΕ4 carriers. Cortex, 57, 167–176. doi: 10.1016/j.cortex.2014.04.006 CrossRefGoogle Scholar
Mahley, R.W. (1988). Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science, 240(4852), 622–630.Google Scholar
Marchant, N.L., King, S.L., Tabet, N., & Rusted, J.M. (2010). Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers. Neuropsychopharmacology, 35(5), 1090–1096. doi: 10.1038/npp.2009.214 CrossRefGoogle ScholarPubMed
Marioni, R.E., Campbell, A., Scotland, G., Hayward, C., Porteous, D.J., & Deary, I.J. (2016). Differential effects of the APOE ε4 allele on different domains of cognitive ability across the life-course. European Journal of Human Genetics, 24, 919–923. doi: 10.1038/ejhg.2015.210 Google Scholar
Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., & Wager, T.D. (2000). The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: A latent variable analysis. Cognitive Psychology, 41(1), 49–100. doi: 10.1006/cogp.1999.0734 Google Scholar
Mondadori, C.R.A., de Quervain, D.J.-F., Buchmann, A., Mustovic, H., Wollmer, M.A., Schmidt, C.F., & Henke, K. (2007). Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cerebral Cortex, 17(8), 1934–1947. doi: 10.1093/cercor/bhl103 Google Scholar
Nichols, L.M., Masdeu, J.C., Mattay, V.S., Kohn, P., Emery, M., Sambataro, F., & Weinberger, D.R. (2012). Interactive effect of apolipoprotein e genotype and age on hippocampal activation during memory processing in healthy adults. Archives of General Psychiatry, 69(8), 804–813.Google Scholar
Oberlin, L.E., Manuck, S.B., Gianaros, P.J., Ferrell, R.E., Muldoon, M.F., Jennings, J.R., & Erickson, K.I. (2015). Blood pressure interacts with APOE ε4 to predict memory performance in a midlife sample. Neuropsychology, 29(5), 693–702. doi: neu0000177 Google Scholar
Panizzon, M.S., Hauger, R., Xian, H., Vuoksimaa, E., Spoon, K.M., Mendoza, S.P., & Franz, C.E. (2014). Interaction of APOE genotype and testosterone on episodic memory in middle-aged men. Neurobiology of Aging, 35(7), 1778.e1–1778.e8. doi:10.1016/j.neurobiolaging.2013.12.025.Google Scholar
Patel, K.T., Stevens, M.C., Pearlson, G.D., Winkler, A.M., Hawkins, K.A., Skudlarski, P., & Bauer, L.O. (2013). Default mode network activity and white matter integrity in healthy middle-aged ApoΕ4 carriers. Brain Imaging and Behavior, 7(1), 60–67. doi: 10.1007/s11682-012-9187-y CrossRefGoogle Scholar
Peila, R., White, L.R., Petrovich, H., Masaki, K., Ross, G.W., Havlik, R.J., & Launer, L.J. (2001). Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: The Honolulu-Asia aging study. Stroke, 32(12), 2882–2889. doi: 10.1161/hs1201.100392 Google Scholar
Protas, H.D., Chen, K., Langbaum, J.B.S., Fleisher, A.S., Alexander, G.E., Lee, W., & Reiman, E.M. (2013). Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurology, 70(3), 320–325. doi: 10.1001/2013.jamaneurol.286 Google Scholar
Puttonen, S., Elovainio, M., Kivimäki, M., Lehtimäki, T., & Keltikangas-Järvinen, L. (2003). The combined effects of apolipoprotein E polymorphism and low-density lipoprotein cholesterol on cognitive performance in young adults. Neuropsychobiology, 48(1), 35–40. doi: 10.1159/000071827 Google Scholar
Ready, R.E., Baran, B., Chaudhry, M., Schatz, K., Gordon, J., & Spencer, R.M.C. (2011). Apolipoprotein E-ε4, processing speed, and white matter volume in a genetically enriched sample of midlife adults. American Journal of Alzheimer’s Disease and Other Dementias, 26(6), 463–468. doi: 10.1177/1533317511421921 CrossRefGoogle Scholar
Rusted, J.M., Evans, S.L., King, S.L., Dowell, N., Tabet, N., & Tofts, P.S. (2013). APOE ε4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. Neuroimage, 65, 364–373. doi: 10.1016/j.neuroimage.2012.10.010 Google Scholar
Sager, M., Hermann, B., & La Rue, A. (2005). Middle-aged children of persons with Alzheimer’s disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer’s Prevention. Journal of Geriatric Psychiatry and Neurology, 18(4), 245–249. doi: 10.1177/0891988705281882 Google Scholar
Schultz, M.R., Lyons, M.J., Franz, C.E., Grant, M.D., Boake, C., Jacobson, K.C., & Kremen, W.S. (2008). Apolipoprotein E genotype and memory in the sixth decade of life. Neurology, 70(19 Pt 2), 1771–1777. doi: 10.1212/01.wnl.0000286941.74372.cc Google Scholar
Shin, M.H., Kweon, S.S., Choi, J.S., Lee, Y.H., Nam, H.S., Park, K.S., & Jeong, S.K. (2014). The effect of an APOE polymorphism on cognitive function depends on age. Journal of Neurology, 261, 66–72. doi: 10.1007/s00415-013-7157-y Google Scholar
Small, B.J., Rosnick, C.B., Fratiglioni, L., & Bäckman, L. (2004). Apolipoprotein E and cognitive performance: A meta-analysis. Psychology and Aging, 19(4), 592–600. doi: 10.1037/0882-7974.19.4.592 CrossRefGoogle ScholarPubMed
Sunderland, T., Mirza, N., Putnam, K.T., Linker, G., Bhupali, D., Durham, R., & Cohen, R.M. (2004). Cerebrospinal fluid ??-amyloid 1-42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ??4 allele. Biological Psychiatry, 56(9), 670–676. doi: 10.1016/j.biopsych.2004.07.021 Google Scholar
Taylor, W.D., Boyd, B., Turner, R., McQuoid, D.R., Ashley-Koch, A., MacFall, J.R., & Potter, G.G. (2016). APOE ε4 associated with preserved executive function performance and maintenance of temporal and cingulate brain volumes in younger adults. Brain Imaging and Behavior. doi: 10.1007/s11682-016-9522-9 Google Scholar
Trachtenberg, A.J., Filippini, N., Cheeseman, J., Duff, E.P., Neville, M.J., Ebmeier, K.P., & Mackay, C.E. (2012). The effects of APOE on brain activity do not simply reflect the risk of Alzheimer’s disease. Neurobiology of Aging, 33(3), 618.e1–618.e13. doi: 10.1016/j.neurobiolaging.2010.11.011 Google Scholar
van Exel, E., de Craen, A.J.M., Gussekloo, J., Houx, P., Bootsma-van der Wiel, A., Macfarlane, P.W., & Westendorp, R.G.J. (2002). Association between high-density lipoprotein and cognitive impairment in the oldest old. Annals of Neurology, 51(6), 716–721. doi: 10.1002/ana.10220 Google Scholar
Velichkovsky, B.B., Roschina, I.F., & Selezneva, N.D. (2015). Cognitive control and memory in healthy ApoE-ε4 carriers with a family history of Alzheimer’s disease. Psychology in Russia: State of the Art, 8(1), 4–13. doi: 10.11621/pir.2015.0101 Google Scholar
Walhovd, K.B., Fjell, A.M., & Espeseth, T. (2014). Cognitive decline and brain pathology in aging--Need for a dimensional, lifespan and systems vulnerability view. Scandinavian Journal of Psychology, 55(3), 244–254. doi: 10.1111/sjop.12120 CrossRefGoogle ScholarPubMed
Whitmer, R.A., Sidney, S., Selby, J., Johnston, S.C., & Yaffe, K. (2005). Midlife cardiovascular risk factors and risk of dementia in late life. Neurology, 64(2), 277–281. doi: 10.1212/01.WNL.0000149519.47454.F2 Google Scholar
Wirth, M., Villeneuve, S., La Joie, R., Marks, S.M., & Jagust, W.J. (2014). Gene-environment interactions: Lifetime cognitive activity, APOE genotype, and β-amyloid burden. The Journal of Neuroscience, 34(25), 8612–8617. doi: 10.1523/JNEUROSCI.4612-13.2014 Google Scholar
Wisdom, N.M., Callahan, J.L., & Hawkins, K.A. (2011). The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiology of Aging, 32(1), 63–74. doi: 10.1016/j.neurobiolaging.2009.02.003 Google Scholar
Xu, G., McLaren, D.G., Ries, M.L., Fitzgerald, M.E., Bendlin, B.B., Rowley, H.A., & Johnson, S.C. (2009). The influence of parental history of Alzheimer’s disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain, 132(Pt 2), 383–391. doi: 10.1093/brain/awn254 Google Scholar
Yan, F.-X., Wu, C.W., Chao, Y.-P., Chen, C.-J., & Tseng, Y.-C. (2015). APOE-ε4 allele altered the rest-stimulus interactions in healthy middle-aged adults. PloS One, 10(6), e0128442. doi: 10.1371/journal.pone.0128442 Google Scholar
Yu, Y.W., Lin, C.H., Chen, S.P., Hong, C.J., & Tsai, S.J. (2000). Intelligence and event-related potentials for young female human volunteer apolipoprotein E epsilon4 and non-epsilon4 carriers. Neuroscience Letters, 294, 179–181. doi: S030439400001569X [pii] Google Scholar
Zade, D., Beiser, A., McGlinchey, R., Au, R., Seshadri, S., Palumbo, C., & Milberg, W. (2010). Interactive effects of apolipoprotein E Type 4 genotype and cerebrovascular risk on neuropsychological performance and structural brain changes. Journal of Stroke and Cerebrovascular Diseases, 19(4), 261–268. doi: 10.1016/j.jstrokecerebrovasdis.2009.05.001 Google Scholar
Zhao, J.H., Brunner, E.J., Kumari, M., Singh-Manoux, A., Hawe, E., Talmud, P.J., & Humphries, S.E. (2005). APOE polymorphism, socioeconomic status and cognitive function in mid-life. The Whitehall II longitudinal study. Social Psychiatry and Psychiatric Epidemiology, 40, 557–563. doi: 10.1007/s00127-005-0925-y Google Scholar
Zuelsdorff, M.L., Engelman, C.D., Friedman, E.M., Koscik, R.L., Jonaitis, E.M., La Rue, A., & Sager, M.A. (2013). Stressful events, social support, and cognitive function in middle-aged adults with a family history of Alzheimer’s disease. Journal of Aging and Health, 25, 944–959. 0898264313498416.Google Scholar