Aim: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. Methods: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini-Mental State Examination scores (control-high group ≥29 and control-low group < 29). Results: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control-high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. Conclusions: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.

Keywords:
APOE genotype, Healthy aging, Cognitive performance, Age, Educational level
1.
Hirono N, Hashimoto M, Yasuda M, Kazui H, Mori E: Accelerated memory decline in Alzheimer’s disease with apolipoprotein ε4 allele. J Neuropsychiatry Clin Neurosci 2003; 15: 354–358.
2.
Reitz C, Mayeux R: Use of genetic variation as biomarkers for mild cognitive impairment and progression of mild cognitive impairment to dementia. J Alzheimers Dis 2010; 19: 229–251.
3.
Anstey K, Christensen H: Education, activity, health, blood pressure and apolipoprotein E as predictors of cognitive change in old age: a review. Gerontology 2000; 46: 163–177.
4.
Negash S, Petersen LE, Geda YE, Knopman DS, Boeve BF, Smith GE, et al: Effects of ApoE genotype and mild cognitive impairment on implicit learning. Neurobiol Aging 2007; 28: 885–893.
5.
Greenwood PM, Parasuraman R: Normal genetic variation, cognition, and aging. Behav Cogn Neurosci Rev 2003; 2: 278–306.
6.
Greenwood PM, Lambert C, Sunderland T, Parasuraman R: 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 2005; 19: 199–211.
7.
Flory JD, Manuck SB, Ferrell RE, Ryan CM, Muldoon MF: Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. Am J Med Genet 2000; 96: 707–711.
8.
Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ, et al: Apolipoprotein E genotype influences cognitive “phenotype” in patients with Alzheimer’s disease but not in healthy control subjects. Neurology 1998; 50: 355–362.
9.
Wilson RS, Mendes de Leon CF, Barnes LL, et al: Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA 2002; 287: 742–748.
10.
Yip AG, Brayne C, Easton D, Rubinsztein DC; Medical Research Council Cognitive Function Ageing Study (MRC CFAS): Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population. J Med Genet 2002; 39: 639–643.
11.
Liu F, Pardo LM, Schuur M, Sanchez-Juan P, Isaacs A, Sleegers K, et al: The apolipoprotein E gene and its age-specific effects on cognitive function. Neurobiol Aging 2010; 31: 1831–1833.
12.
Valenzuela MJ, Sachdev P: Brain reserve and cognitive decline: a non-parametric systematic review. Psychol Med 2006; 36: 1065–1073.
13.
Stern Y: What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2002; 8: 448–460.
14.
Fratiglioni L, Wang H-X: Brain reserve hypothesis in dementia. J Alzheimers Dis 2007; 12: 11–22.
15.
Sattler C, Toro P, Schönknecht P, Schröder J: Cognitive activity, education and socioeconomic status as pre ventive factors for mild cognitive impairment and Alzheimer’s disease. Psychiatry Res 2012; 196: 90–95.
16.
Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R: Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA 1994; 271: 1004–1010.
17.
Muniz-Terrera G, Matthews F, Dening T, Huppert FA, Brayne C; CC75C Group: Education and trajectories of cognitive decline over 9 years in very old people: methods and risk analysis. Age Ageing 2009; 38: 277–282.
18.
Katzman R: Education and the prevalence of dementia and Alzheimer’s disease. Neurology 1993; 43: 13–20.
19.
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
20.
Oldfield RC: The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.
21.
López ME, Turrero A, Cuesta P, López-Sanz D, Bruña R, Marcos A, et al: Searching for primary predictors of conversion from mild cognitive impairment to Alzheimer’s disease: a multivariate follow-up study. J Alzheimers Dis 2016; 52: 133–143.
22.
Wechsler D: Wechsler Memory Scale – Third Edition Manual. Orlando, The Psychological Corporation, 1997.
23.
Benton A, Hamsher K: Multilingual Aphasia Examination, ed 2. Iowa City, Benton & Hamsher, 1989.
24.
Peña-Casanova J: Programa Integrado de Exploración Neuropsicológica – Test Barcelona. Protocolo. Barcelona, Masson, 1990.
25.
Warrington E, James M: The Visual Object and Space Perception Battery. Bury St. Edmunds, Thames Valley Test Company, 1991.
26.
Kaplan E, Goodglass H, Weintraub S: The Boston Naming Test. Philadelphia, Lea and Febiger, 1983.
27.
Reitan R: Validity of the Trail Making test as an indicator of organic brain damage. Percept Mot Ski 1958; 8: 271–276.
28.
Sunderland A, Harris JE, Gleave J: Memory failures in everyday life following severe head injury. J Clin Neuropsychol 1984; 6: 127–142.
29.
Rami L, Mollica MA, Garcfa-Sanchez C, Saldafia J, Sanchez B, Sala I, et al: The subjective cognitive decline questionnaire (SCD-Q): a validation study. J Alzheimers Dis 2014; 41: 453–466.
30.
Jack CR, Albert MS, Knopman DS, McKhann GM, Sperling R, Carrillo MC, et al: Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 257–262.
31.
Jessen F, Amariglio RE, Van Boxtel M, Breteler M, Ceccaldi M, Chételat G, et al: A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement 2014; 10: 844–852.
32.
Molinuevo JL, Rabin LA, Amariglio R, Buckley R, Dubois B, Ellis KA, et al: Implementation of subjective cognitive decline criteria in research studies. Alzheimers Dement 2017; 13: 296–311.
33.
Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B: Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis. Acta Psychiatr Scand 2014; 130: 439–451.
34.
Eckerström M, Göthlin M, Rolstad S, Hessen E, Eckerström C, Nordlund A, et al: Longitudinal evaluation of criteria for subjective cognitive decline and preclinical Alzheimer’s disease in a memory clinic sample. Alzheimers Dement (Amsterdam) 2017; 8: 96–107.
35.
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A: Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980; 7: 486–488.
36.
Hixson JE, Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990; 31: 545–548.
37.
Grothe MJ, Villeneuve S, Dyrba M, Bartrés-Faz D, Wirth M; Alzheimer’s Disease Neuroimaging Initiative: Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology 2017; 88: 569–576.
38.
Suri S, Heise V, Trachtenberg AJ, Mackay CE: The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE ɛ2. Neurosci Biobehav Rev 2013; 37: 2878–2886.
39.
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al: Whole brain segmentation. Neuron 2002; 33: 341–355.
40.
Mickey RM, Greenland S: The impact of confounder selection criteria on effect estimation. Am J Epidemiol 1989; 129: 125–137.
41.
Winnock M, Letenneur L, Jacqmin-Gadda H, Dallongeville J, Amouyel P, Dartigues JF: Longitudinal analysis of the effect of apolipoprotein E epsilon4 and education on cognitive performance in elderly subjects: the PAQUID study. J Neurol Neurosurg Psychiatry 2002; 72: 794–797.
42.
Bunce D, Fratiglioni L, Small BJ, Winblad B, Bäckman L: APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology 2004; 63: 816–821.
43.
Hayden KM, Zandi PP, West NA, Tschanz JT, Norton MC, Corcoran C, et al: Effects of family history and apolipoprotein E epsilon4 status on cognitive decline in the absence of Alzheimer dementia: the Cache County Study. Arch Neurol 2009; 66: 1378–1383.
44.
Foster JK, Albrecht MA, Savage G, Lautenschlager NT, Ellis KA, Maruff P, et al: Lack of reliable evidence for a distinctive ε4-related cognitive phenotype that is independent from clinical diagnostic status: findings from the Australian Imaging, Biomarkers and Lifestyle Study. Brain 2013; 136: 2201–2216.
45.
Lopez MN, Charter RA, Mostafavi B, Nibut LP, Smith WE: Psychometric properties of the Folstein Mini-Mental State Examination. Assessment 2005; 12: 137–144.
46.
Roalf DR, Moberg PJ, Xie SX, Wolk DA, Moelter ST, Arnold SE: Comparative accuracies of two common screen ing instruments for classification of Alzheimer’s disease, mild cognitive impairment, and healthy aging. Alz heimers Dement 2013; 9: 529–537.
47.
Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, et al: APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 2010; 67: 122–131.
48.
Tosun D, Schuff N, Truran-Sacrey D, Shaw LM, Trojanowski JQ, Aisen P, et al: Relations between brain tissue loss, CSF biomarkers, and the ApoE genetic profile: a longitudinal MRI study. Neurobiol Aging 2010; 31: 1340–1354.
49.
Curtiss LK, Boisvert WA: Apolipoprotein E and atherosclerosis. Curr Opin Lipidol 2000; 11: 243–251.
50.
Han X: Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipidomics. J Neurochem 2007; 103: 171–179.
51.
Aono M, Lee Y, Grant ER, Zivin RA, Pearlstein RD, Warner DS, et al: Apolipoprotein E protects against NMDA excitotoxicity. Neurobiol Dis 2002; 11: 214–220.
52.
Bagepally BS, Halahalli HN, John JP, Kota L, Purushottam M, Mukherjee O, et al: Apolipoprotein E4 and brain white matter integrity in Alzheimer’s disease: tract-based spatial statistics study under 3-Tesla MRI. Neurodegener Dis 2012; 10: 145–148.
53.
Crawford FC, Vanderploeg RD, Freeman MJ, Singh S, Waisman M, Michaels L, et al: APOE genotype influences acquisition and recall following traumatic brain injury. Neurology 2002; 58: 1115–1118.
54.
López-Higes R, Rodríguez-Rojo IC, Prados JM, Montejo P, Del-Río D, Delgado-Losada ML, et al: APOE ε4 modulation of training outcomes in several cognitive domains in a sample of cognitively intact older adults. J Alzheimers Dis 2017; 58: 1201–1215.
55.
Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, et al: Cognitive change and the APOE epsilon 4 allele. Nature 2002; 418: 932.
56.
Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, et al: Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med 2009; 361: 255–263.
57.
Schiepers OJG, Harris SE, Gow AJ, Pattie A, Brett CE, Starr JM, et al: APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921. Mol Psychiatry 2012; 17: 315–324.
58.
Bondi MW, Salmon DP, Monsch AU, Galasko D, Butters N, Klauber MR, et al: Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults. Neurology 1995; 45: 2203–2206.
59.
Bäckman L, Wahlin Å, Small BJ, Herlitz A, Winblad B, Fratiglioni L: Cognitive functioning in aging and dementia: The Kungsholmen Project. Aging Neuropsychol Cogn 2004; 11: 212–244.
60.
Hayden KM: Effects of family history and apolipoprotein E ε4 status on cognitive decline in the absence of Alzheimer dementia. Arch Neurol 2009; 66: 1378.
61.
Bretsky P, Guralnik JM, Launer L, Albert M, Seeman TE; MacArthur Studies of Successful Aging: The role of APOE-epsilon4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging. Neurology 2003; 60: 1077–1081.
62.
Small BJ, Rosnick CB, Fratiglioni L, Bäckman L: Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 2004; 19: 592–600.
63.
Wisdom NM, Callahan JL, Hawkins KA: The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis. Neurobiol Aging 2011; 32: 63–74.
64.
Nordlund A, Rolstad S, Klang O, Edman A, Hansen S, Wallin A: Two-year outcome of MCI subtypes and aetiologies in the Göteborg MCI study. J Neurol Neurosurg Psychiatry 2010; 81: 541–546.
65.
Bartrés-Faz D, Arenaza-Urquijo EM: Structural and functional imaging correlates of cognitive and brain reserve hypotheses in healthy and pathological aging. Brain Topogr 2011; 24: 340–357.
66.
Meng X, D’Arcy C: Education and dementia in the context of the cognitive reserve hypothesis: a systematic review with meta-analyses and qualitative analyses. PLoS One 2012; 7:e38268.
67.
Bruandet A, Richard F, Bombois S, Maurage CA, Masse I, Amouyel P, et al: Cognitive decline and survival in Alzheimer’s disease according to education level. Dement Geriatr Cogn Disord 2008; 25: 74–80.
68.
Valenzuela MJ, Sachdev P, Wen W, Chen X, Brodaty H: Lifespan mental activity predicts dimished rate of hippocamapal atrophy. PLoS One 2008; 3:e2598.
69.
Ihle A, Oris M, Fagot D, Baeriswyl M, Guichard E, Kliegel M: The association of leisure activities in middle adulthood with cognitive performance in old age: the moderating role of educational level. Gerontology 2015; 61: 543–550.
70.
Rouillard M, Audiffren M, Albinet C, Ali Bahri M, Garraux G, Collette F: Contribution of four lifelong factors of cognitive reserve on late cognition in normal aging and Parkinson’s disease. J Clin Exp Neuropsychol 2017; 39: 142–162.
71.
Amieva H, Letenneur L, Dartigues J-F, Rouch-Leroyer I, Sourgen C, D’Alchée-Birée F, et al: Annual rate and predictors of conversion to dementia in subjects presenting mild cognitive impairment criteria defined according to a population-based study. Dement Geriatr Cogn Disord 2004; 18: 87–93.
72.
Vaqué-Alcázar L, Sala-Llonch R, Valls-Pedret C, Vidal-Piñeiro D, Fernández-Cabello S, Bargalló N, et al: Differential age-related gray and white matter impact mediates educational influence on elders’ cognition. Brain Imaging Behav 2017; 11: 318–332.
73.
Buckner RL, Louis S: Memory and executive function review in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 2004; 44: 195–208.
74.
Bender AR, Raz N: 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 2012; 50: 704–714.
75.
GC W: Pleiotropy, natural selection and evolution of senescence. Evolution 1957; 11: 398–411.
76.
Evans S, Dowell NG, Tabet N, Tofts PS, King SL, Rusted JM: Cognitive and neural signatures of the APOE E4 allele in mid-aged adults. Neurobiol Aging 2014; 35: 1615–1623.
77.
Hassenstab J, Chasse R, Grabow P, Benzinger TLS, Fagan AM, Xiong C, et al: Certified normal: Alzheimer’s disease biomarkers and normative estimates of cognitive functioning. Neurobiol Aging 2016; 43: 23–33.
78.
Lim YY, Laws SM, Villemagne VL, Pietrzak RH, Porter T, Ames D, et al: Aβ-related memory decline in APOE ε4 noncarriers: implications for Alzheimer disease. Neurology 2016; 86: 1635–1642.
79.
Soldan A, Pettigrew C, Cai Q, Wang M-C, Moghekar AR, O’Brien RJ, et al: Hypothetical preclinical Alzheimer disease groups and longitudinal cognitive change. JAMA Neurol 2016; 73: 698–705.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.