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

  • Claire Lancaster (a1), Naji Tabet (a2) and Jennifer Rusted (a1)
Abstract
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)

Copyright
Corresponding author
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
References
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AlexanderD.M., WilliamsL.M., GattJ.M., Dobson-StoneC., KuanS.A., ToddE.G., & GordonE. (2007). The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biological Psychology, 75(3), 229238. doi: 10.1016/j.biopsycho.2007.03.001
Alzheimer’s Society. (2016). Alzheimersorguk. Retrieved 5 April, 2016, from https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=341.
AtzmonG., GabrielyI., GreinerW., DavidsonD., SchechterC., & BarzilaiN. (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), 712715. doi: 10.1093/gerona/57.11.M712
BenderA.R., & RazN. (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), 704714. doi: 10.1016/j.neuropsychologia.2011.12.025
BlairC.K., FolsomA.R., KnopmanD.S., BrayM.S., MosleyT.H., & BoerwinkleE. (2005). APOE genotype and cognitive decline in a middle-aged cohort. Neurology, 64(2), 268276. doi: 10.1212/01.WNL.0000149643.91367.8A
BorensteinM., HedgesL., HigginsJ., & RothsteinH. (2009). Complex data structures, Introduction to meta-analysis (pp. 215245). West Sussex, UK: John Wiley & Sons Ltd.
BunceD., AnsteyK.J., BurnsR., ChristensenH., & EastealS. (2011). Does possession of apolipoprotein E ɛ4 benefit cognitive function in healthy young adults? Neuropsychologia, 49(7), 16931697. doi: 10.1016/j.neuropsychologia.2011.02.042
BunceD., BielakA.A.M., AnsteyK.J., CherbuinN., BatterhamP.J., & EastealS. (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), 379386. doi: 10.1093/gerona/glt103
BunceD., KivipeltoM., & WahlinA. (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), 362370. doi: 10.1037/0894-4105.18.2.362
CaselliR.J., ChenK., LeeW., AlexanderG.E., & ReimanE.M. (2008). Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre–mild cognitive impairment. Archives of Neurology, 65(9), 12311236.
CaselliR.J., ChenK., LockeD.E.C., LeeW., RoontivaA., BandyD., & ReimanE.M. (2014). Subjective cognitive decline: Self and informant comparisons. Alzheimer’s & Dementia, 10(1), 9398.
CaselliR.J., DueckA.C., LockeD.E.C., Hoffman-SnyderC.R., WoodruffB.K., RapcsakS.Z., & ReimanE.M. (2011). Longitudinal modeling of frontal cognition in APOE ϵ4 homozygotes, heterozygotes, and noncarriers. Neurology, 76(16), 13831388. doi: 10.1212/WNL.0b013e3182167147
CaselliR.J., DueckA.C., OsborneD., SabbaghM.N., ConnorD.J., AhernG.L., & ReimanE.M. (2009). Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. The New England Journal of Medicine, 361, 255263. doi: 10.1016/S0084-3954(09)79603-4
CaselliR.J., Graff–RadfordN.R., ReimanE.M., WeaverA., OsborneD., LucasJ., & ThibodeauS.N. (1999). Preclinical memory decline in cognitively normal apolipoprotein E–ε4 homozygotes. Neurology, 53(1), 201.
ChenC.-J., ChenC.-C., WuD., ChiN.-F., ChenP.-C., LiaoY.-P., & HuC.-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), 11971202. doi: 10.3174/ajnr.A3369
CorderE.H., SaundersA.M., StrittmatterW.J., SchmechelD.E., GaskellP.C., SmallG., & Pericak-VanceM. (1993). Gene does of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921923.
DeCosterJ. (2009). Meta-analysis notes. Retrieved 07/28/2016 from http://www.stat-help.com/notes.html.
DeenyS.P., PoeppelD., ZimmermanJ.B., RothS.M., BrandauerJ., WitkowskiS., & BrandtJ. (2008). Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers. Biological Psychology, 78(2), 179187.
DonixM., BurggrenA.C., SuthanaN.A., SiddarthP., EkstromA.D., KrupaA.K., & BookheimerS.Y. (2010). Family history of Alzheimer’s disease and hippocampal structure in healthy people. American Journal of Psychiatry, 167(11), 13991406. doi: 10.1176/appi.ajp.2010.09111575
EvansS., DowellN.G., TabetN., ToftsP.S., KingS.L., GrayM., & RustedJ.M. (2013). Nicotine effects on attentional reorienting in mid-age adults, and interactions with apolipoprotein E status. Journal of Psychopharmacology (Oxford, England), 27(11), 10071014. doi: 10.1177/0269881113499828
EvansS., DowellN.G., TabetN., ToftsP.S., KingS.L., & RustedJ.M. (2014). Cognitive and neural signatures of the APOE Ε4 allele in mid-aged adults. Neurobiology of Aging, 35(7), 16151623. doi: 10.1016/j.neurobiolaging.2014.01.145
FarrerL.A., CupplesL.A., HainesJ.L., HymanB., KukullW.A., MayeuxR., & van DuijnC.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), 13491356. doi: 10.1001/jama.1997.03550160069041
FloryJ.D., ManuckS.B., FerrellR.E., RyanC.M., & MuldoonM.F. (2000). Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. American Journal of Medical Genetics, 96(6), 707711. doi: 10.1002/1096-8628(20001204)96:6<707::AID-AJMG1>3.0.CO;2-V
De FriasC.M., SchaieK.W., & WillisS.L. (2014). Hypertension moderates the effect of APOE on 21-year cognitive trajectories. Psychology and Aging, 29(2), 431439. doi: 10.1037/a0036828
GoveasJ.S., XieC., ChenG., LiW., WardB.D., FranczakM.B., & LiS.-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
GreenwoodP.M., SunderlandT., FrizJ.L., & ParasuramanR. (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), 1166111666.
GreenwoodP.M., LambertC., SunderlandT., & ParasuramanR. (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), 199211.
GreenwoodP.M., EspesethT., LinM.-K., ReinvangI., & ParasuramanR. (2014). Longitudinal change in working memory as a function of APOE genotype in midlife and old age. Scandinavian Journal of Psychology, 55(3), 268277. doi: 10.1111/sjop.12123
GreenwoodP.M., SunderlandT., PutnamK., LevyJ., & ParasuramanR. (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), 830840. doi: 10.1037/0894-4105.19.6.830
HanS.D., & BondiM.W. (2008). Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimer’s & Dementia, 4(4), 251254. doi: 10.1016/j.jalz.2008.02.006
HanS.D., DrakeA.I., CessanteL.M., JakA.J., HoustonW.S., DelisD.C., & BondiM.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), 11031108. doi: 10.1136/jnnp.2006.108183
HerrupK. (2010). Reimagining Alzheimer’s disease--An age-based hypothesis. Journal of Neuroscience, 30(50), 1675516762. doi: 10.1523/JNEUROSCI.4521-10.2010
HubacekJ.A., PithaJ., ŠkodováZ., AdámkováV., LánskáV., & PoledneR. (2001). A possible role of apolipoprotein E polymorphism in predisposition to higher education. Neuropsychobiology, 43(3), 200203. doi: 10.1159/000054890
IhleA., BunceD., & KliegelM. (2012). APOE ε4 and cognitive function in early life: A meta-analysis. Neuropsychology, 26(3), 267277. doi: 10.1037/a0026769
JochemsenH.M., MullerM., van der GraafY., & GeerlingsM.I. (2012). APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiology of Aging, 33(4), 832.e15e22. doi: 10.1016/j.neurobiolaging.2011.07.016
JormA.F., MatherK.A., ButterworthP., AnsteyK.J., ChristensenH., & EastealS. (2007). APOE genotype and cognitive functioning in a large age-stratified population sample. Neuropsychology, 21(1), 18. doi: 10.1037/0894-4105.21.1.1
KöhlerS., BaarsM.A.E., SpauwenP., SchievinkS., VerheyF.R.J., & van BoxtelM.J.P. (2014). Temporal evolution of cognitive changes in incident hypertension: Prospective cohort study across the adult age span. Hypertension, 63(2), 245251. doi: 10.1161/HYPERTENSIONAHA.113.02096
KozauerN.A., MielkeM.M., ChanG.K.C., RebokG.W., & LyketsosC.G. (2008). Apolipoprotein E genotype and lifetime cognitive decline. International Psychogeriatrics, 20(01), 109123. doi: 10.1017/S104161020700587X
LangbaumJ.B.S., ChenK., CaselliR.J., LeeW., ReschkeC., BandyD., & ReederS.A. (2010). Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E ε4 allele. Archives of Neurology, 67(4), 462468.
LevyJ.A., BergesonJ., PutnamK., RosenV., CohenR., LalondeF., & SunderlandT. (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), 362370. doi: 10.1017/S1355617704103044
LiW., AntuonoP.G., XieC., ChenG., JonesJ.L., WardB.D., & LiS.-J. (2014). Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOΕ4 carriers. Cortex, 57, 167176. doi: 10.1016/j.cortex.2014.04.006
MahleyR.W. (1988). Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science, 240(4852), 622630.
MarchantN.L., KingS.L., TabetN., & RustedJ.M. (2010). Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers. Neuropsychopharmacology, 35(5), 10901096. doi: 10.1038/npp.2009.214
MarioniR.E., CampbellA., ScotlandG., HaywardC., PorteousD.J., & DearyI.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, 919923. doi: 10.1038/ejhg.2015.210
MiyakeA., FriedmanN.P., EmersonM.J., WitzkiA.H., HowerterA., & WagerT.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), 49100. doi: 10.1006/cogp.1999.0734
MondadoriC.R.A., de QuervainD.J.-F., BuchmannA., MustovicH., WollmerM.A., SchmidtC.F., & HenkeK. (2007). Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cerebral Cortex, 17(8), 19341947. doi: 10.1093/cercor/bhl103
NicholsL.M., MasdeuJ.C., MattayV.S., KohnP., EmeryM., SambataroF., & WeinbergerD.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), 804813.
OberlinL.E., ManuckS.B., GianarosP.J., FerrellR.E., MuldoonM.F., JenningsJ.R., & EricksonK.I. (2015). Blood pressure interacts with APOE ε4 to predict memory performance in a midlife sample. Neuropsychology, 29(5), 693702. doi: neu0000177
PanizzonM.S., HaugerR., XianH., VuoksimaaE., SpoonK.M., MendozaS.P., & FranzC.E. (2014). Interaction of APOE genotype and testosterone on episodic memory in middle-aged men. Neurobiology of Aging, 35(7), 1778.e11778.e8. doi:10.1016/j.neurobiolaging.2013.12.025.
PatelK.T., StevensM.C., PearlsonG.D., WinklerA.M., HawkinsK.A., SkudlarskiP., & BauerL.O. (2013). Default mode network activity and white matter integrity in healthy middle-aged ApoΕ4 carriers. Brain Imaging and Behavior, 7(1), 6067. doi: 10.1007/s11682-012-9187-y
PeilaR., WhiteL.R., PetrovichH., MasakiK., RossG.W., HavlikR.J., & LaunerL.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), 28822889. doi: 10.1161/hs1201.100392
ProtasH.D., ChenK., LangbaumJ.B.S., FleisherA.S., AlexanderG.E., LeeW., & ReimanE.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), 320325. doi: 10.1001/2013.jamaneurol.286
PuttonenS., ElovainioM., KivimäkiM., LehtimäkiT., & Keltikangas-JärvinenL. (2003). The combined effects of apolipoprotein E polymorphism and low-density lipoprotein cholesterol on cognitive performance in young adults. Neuropsychobiology, 48(1), 3540. doi: 10.1159/000071827
ReadyR.E., BaranB., ChaudhryM., SchatzK., GordonJ., & SpencerR.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), 463468. doi: 10.1177/1533317511421921
RustedJ.M., EvansS.L., KingS.L., DowellN., TabetN., & ToftsP.S. (2013). APOE ε4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. Neuroimage, 65, 364373. doi: 10.1016/j.neuroimage.2012.10.010
SagerM., HermannB., & La RueA. (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), 245249. doi: 10.1177/0891988705281882
SchultzM.R., LyonsM.J., FranzC.E., GrantM.D., BoakeC., JacobsonK.C., & KremenW.S. (2008). Apolipoprotein E genotype and memory in the sixth decade of life. Neurology, 70(19 Pt 2), 17711777. doi: 10.1212/01.wnl.0000286941.74372.cc
ShinM.H., KweonS.S., ChoiJ.S., LeeY.H., NamH.S., ParkK.S., & JeongS.K. (2014). The effect of an APOE polymorphism on cognitive function depends on age. Journal of Neurology, 261, 6672. doi: 10.1007/s00415-013-7157-y
SmallB.J., RosnickC.B., FratiglioniL., & BäckmanL. (2004). Apolipoprotein E and cognitive performance: A meta-analysis. Psychology and Aging, 19(4), 592600. doi: 10.1037/0882-7974.19.4.592
SunderlandT., MirzaN., PutnamK.T., LinkerG., BhupaliD., DurhamR., & CohenR.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), 670676. doi: 10.1016/j.biopsych.2004.07.021
TaylorW.D., BoydB., TurnerR., McQuoidD.R., Ashley-KochA., MacFallJ.R., & PotterG.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
TrachtenbergA.J., FilippiniN., CheesemanJ., DuffE.P., NevilleM.J., EbmeierK.P., & MackayC.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.e1618.e13. doi: 10.1016/j.neurobiolaging.2010.11.011
van ExelE., de CraenA.J.M., GusseklooJ., HouxP., Bootsma-van der WielA., MacfarlaneP.W., & WestendorpR.G.J. (2002). Association between high-density lipoprotein and cognitive impairment in the oldest old. Annals of Neurology, 51(6), 716721. doi: 10.1002/ana.10220
VelichkovskyB.B., RoschinaI.F., & SeleznevaN.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), 413. doi: 10.11621/pir.2015.0101
WalhovdK.B., FjellA.M., & EspesethT. (2014). Cognitive decline and brain pathology in aging--Need for a dimensional, lifespan and systems vulnerability view. Scandinavian Journal of Psychology, 55(3), 244254. doi: 10.1111/sjop.12120
WhitmerR.A., SidneyS., SelbyJ., JohnstonS.C., & YaffeK. (2005). Midlife cardiovascular risk factors and risk of dementia in late life. Neurology, 64(2), 277281. doi: 10.1212/01.WNL.0000149519.47454.F2
WirthM., VilleneuveS., La JoieR., MarksS.M., & JagustW.J. (2014). Gene-environment interactions: Lifetime cognitive activity, APOE genotype, and β-amyloid burden. The Journal of Neuroscience, 34(25), 86128617. doi: 10.1523/JNEUROSCI.4612-13.2014
WisdomN.M., CallahanJ.L., & HawkinsK.A. (2011). The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiology of Aging, 32(1), 6374. doi: 10.1016/j.neurobiolaging.2009.02.003
XuG., McLarenD.G., RiesM.L., FitzgeraldM.E., BendlinB.B., RowleyH.A., & JohnsonS.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), 383391. doi: 10.1093/brain/awn254
YanF.-X., WuC.W., ChaoY.-P., ChenC.-J., & TsengY.-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
YuY.W., LinC.H., ChenS.P., HongC.J., & TsaiS.J. (2000). Intelligence and event-related potentials for young female human volunteer apolipoprotein E epsilon4 and non-epsilon4 carriers. Neuroscience Letters, 294, 179181. doi: S030439400001569X [pii]
ZadeD., BeiserA., McGlincheyR., AuR., SeshadriS., PalumboC., & MilbergW. (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), 261268. doi: 10.1016/j.jstrokecerebrovasdis.2009.05.001
ZhaoJ.H., BrunnerE.J., KumariM., Singh-ManouxA., HaweE., TalmudP.J., & HumphriesS.E. (2005). APOE polymorphism, socioeconomic status and cognitive function in mid-life. The Whitehall II longitudinal study. Social Psychiatry and Psychiatric Epidemiology, 40, 557563. doi: 10.1007/s00127-005-0925-y
ZuelsdorffM.L., EngelmanC.D., FriedmanE.M., KoscikR.L., JonaitisE.M., La RueA., & SagerM.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, 944959. 0898264313498416.
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