Background: The effect of APOE Ε4 allele (Ε4) on spatial navigation in amnestic mild cognitive impairment (aMCI) is unknown. Objective: Our purpose was to examine the characteristics of spatial navigation impairment in Ε4-positive (Ε4+) and Ε4-negative (Ε4–) aMCI subgroups. Methods: Blood samples were collected to determine the APOE genotype. A total of 34 aMCI patients were stratified into aMCI-Ε4– (n = 23) and aMCI-Ε4+ (n = 11) groups. Control (n = 28) and mild Alzheimer’s disease (AD; n = 16) groups were also used. We used a human analogue of the Morris water maze (enclosed arena 2.9 m in diameter) to examine body-centered (egocentric) and world-centered (allocentric) spatial navigation. Results: The aMCI-Ε4+ group performed poorer on spatial navigation than the aMCI-Ε4– group in both egocentric and allocentric tasks even though these 2 groups did not differ in global cognitive functioning or neuropsychological tests. The aMCI-Ε4+ and mild AD groups performed similarly on all Morris Water Maze tasks and were outperformed by the aMCI-Ε4– group, which also resembled the control group in performance on the egocentric tasks. The aMCI groups showed poor spatial navigation learning regardless of their Ε4 positivity. Conclusion: We found more profound deficits in spatial navigation in aMCI-Ε4+ relative to aMCI-Ε4– patients. The aMCI-Ε4+ group resembled the mild AD group in spatial navigation performance. Although the Ε4 genotype was indicative of spatial navigation performance, it was not indicative of the aMCI patients’ ability to learn the tasks. Spatial navigation testing represents a promising area with respect to identifying individuals at higher risk for AD among the heterogeneous MCI population.

Keywords:
Mild cognitive impairment, Apolipoprotein E, Spatial navigation, Alzheimer’s disease, Morris water maze, Memory
1.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–923.
2.
Saunders AM, Hulette O, Welsh-Bohmer KA, Schmechel DE, Crain B, Burke JR, Alberts MJ, Strittmatter WJ, Breitner JC, Rosenberg C: Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer’s disease. Lancet 1996;348:90–93.
3.
Bondi MW, Salmon DP, Monsch AU, Galasko D, Butters N, Klauber MR, Thal LJ, Saitoh T: Episodic memory changes are associated with the APOE-e4 allele in nondemented older adults. Neurology 1995;45:2203–2206.
4.
Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG: Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology 2004;62:1990–1995.
5.
Petersen RC, Smith GE, Ivnik RJ, Tangalos EG, Schaid DJ, Thibodeau SN, Kokmen E, Waring SC, Kurland LT: Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA 1995;273:1274–1278.
6.
Monacelli AM, Cushman LA, Kavcic V, Duffy CJ: Spatial disorientation in Alzheimer’s disease: the remembrance of things passed. Neurology 2003;61:1491–1497.
7.
Hort J, Laczó J, Vyhnálek M, Bojar M, Bures J, Vlcek K: Spatial navigation deficit in amnestic mild cognitive impairment. Proc Natl Acad Sci USA 2007;104:4042–4047.
8.
Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas RE, Mahley RW, Mucke L: Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci USA 1998;95:10914–10919.
9.
Raber J, Wong D, Yu GQ, Buttini M, Mahley RW, Pitas RE, Mucke L: Alzheimer’s disease: apolipoprotein E and cognitive performance. Nature 2000;404:352–354.
10.
Berteau-Pavy F, Park B, Raber J: Effects of sex and APOE ε4 on object recognition and spatial navigation in the elderly. Neuroscience 2007;147:6–17.
11.
O’Keefe J, Dostrovsky J: The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res 1971;34:171–175.
12.
Morris RG, Garrud P, Rawlins JN, O’Keefe J: Place navigation impaired in rats with hippocampal lesions. Nature 1982;297:681–683.
13.
Laczó J, Andel R, Vyhnalek M, Vlcek K, Magerova H, Varjassyova A, Tolar M, Hort J: Human analogue of the Morris water maze for testing subjects at risk of Alzheimer’s disease. Neurodegener Dis 2010;7:148–152.
14.
Yesavage JA: Geriatric Depression Scale. Psychopharmacol Bull 1988;24:709–711.
15.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
16.
Petersen RC: Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–194.
17.
Hixson JE, Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res 1990;31:545–548.
18.
Stepankova K, Pastalkova E, Kalova E, Kalina M, Bures J: A battery of tests for quantitative examination of idiothetic and allothetic place navigation modes in humans. Behav Brain Res 2003;147:95–105.
19.
Laczó J, Hort J, Vlcek K, Vyhnalek M, Bojar M, Vajnerova O, Holmerova I, Horinek D, Kalina M, Bures J: Spatial memory impairment in Alzheimer’s disease is detectable even in patients with mild cognitive impairment. Cesk Slov Neurol N 2006;102:431–437.
20.
Kalová E, Vlcek K, Jarolímová E, Bures J: Allothetic orientation and sequential ordering of places is impaired in early stages of Alzheimer’s disease: corresponding results in real space tests and computer tests. Behav Brain Res 2005;159:175–186.
21.
Laczó J, Vlcek K, Vyhnálek M, Vajnerová O, Ort M, Holmerová I, Tolar M, Andel R, Bojar M, Hort J: Spatial navigation testing discriminates two types of amnestic mild cognitive impairment. Behav Brain Res 2009;202:252–259.
22.
Bondi MW, Salmon DP, Galasko D, Thomas RG, Thal LJ: Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer’s disease. Psychol Aging 1999;14:295–303.
23.
Kim KW, Youn JC, Jhoo JH, Lee DY, Lee KU, Lee JH, Woo JI: Apolipoprotein E ε4 allele is not associated with cognitive impairment in community-dwelling normal elderly individuals. Int J Geriatr Psychiatry 2002;17:635–640.
24.
Delpolyi AR, Rankin KP, Mucke L, Miller BL, Gorno-Tempini ML: Spatial cognition and the human navigation network in AD and MCI. Neurology 2007;69:986–997.
25.
Caselli RJ, Graff-Radford NR, Reiman EM, Weaver A, Osborne D, Lucas J, Uecker A, Thibodeau SN: Preclinical memory decline in cognitive normal apolipoprotein E-e4 homozygotes. Neurology 1999;53:201–207.
26.
Jonker C, Schmand B, Lindeboom J, Havekes LM, Launer LJ: Association between apolipoprotein E ε4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Arch Neurol 1998;55:1065–1069.
27.
Small BJ, Graves AB, McEvoy CL, Crawford FC, Mullan M, Mortimer JA: Is ApoE-ε4 a risk factor for cognitive impairment in normal aging? Neurology 2000;54:2082–2088.
28.
Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ, Petersen RC: Apolipoprotein E genotype influences cognitive ‘phenotype’ in patients with Alzheimer’s disease but not in healthy controls. Neurology 1998;50:355–362.
29.
Small BJ, Rosnick CB, Fratiglioni L, Bäckman L: Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 2004;19:592–600.
30.
Greenwood PM, Sunderland T, Friz JL, Parasuraman R: Genetics and visual attention: selective deficits in healthy adult carriers of the ε4 allele of the apolipoprotein E gene. Proc Natl Acad Sci USA 2000;97:11661–11666.
31.
Parasuraman R, Greenwood PM, Sunderland T: The apolipoprotein E gene, attention, and brain function. Neuropsychology 2002;16:254–274.
32.
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.
33.
Wolk DA, Dickerson BC; Alzheimer’s Disease Neuroimaging Initiative: Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci USA 2010;107:10256–10261.
34.
Van der Vlies AE, Pijnenburg YAL, Koene T, Klein M, Kok A, Scheltens P, van der Flier WM: Cognitive impairment in Alzheimer’s disease is modified by APOE genotype. Dement Geriatr Cogn Disord 2007;24:98–103.
35.
Tierney MC, Szalai JP, Snow WG, Fisher RH, Tsuda T, Chi H, McLachlan DR, St George-Hyslop PH: A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology 1996;46:149–154.
36.
Astur RS, Taylor LB, Mamelak AN, Philpott L, Sutherland RJ: Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task. Behav Brain Res 2002;132:77–84.
37.
Feigenbaum JD, Morris RG: Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans. Neuropsychology 2004;18:462–472.
38.
Burgess N, Jeffery KJ, O’Keefe J: The Hippocampal and Parietal Foundations of Spatial Cognition, ed 1. Oxford, Oxford University Press, 1999.
39.
Aguirre GK, D’Esposito M: Topographical disorientation: a synthesis and taxonomy. Brain 1999;122:1613–1628.
40.
Ibáñez V, Pietrini P, Alexander GE, Furey ML, Teichberg D, Rajapakse JC, Rapoport SI, Schapiro MB, Horwitz B: Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology 1998;50:1585–1593.
41.
Rossor MN, Kennedy AM, Frackowiak RS: Clinical and neuroimaging features of familial Alzheimer’s disease. Ann NY Acad Sci 1996;777:49–56.
42.
Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME: Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2000;97:6037–6042.
43.
Rapoport SI: Functional brain imaging to identify affected subjects genetically at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2000;97:5690–5698.
© 2010 S. Karger AG, Basel
2010
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.