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Vol. 34, No. 1, 2010
Issue release date: January 2010
Section title: Original Paper
Free Access
Neuroepidemiology 2010;34:43–49
(DOI:10.1159/000256662)

The APOE ε4 Allele Is Associated with Incident Mild Cognitive Impairment among Community-Dwelling Older Persons

Boyle P.A.a, d · Buchman A.S.b, d · Wilson R.S.a, b, d · Kelly J.F.c, d · Bennett D.A.b, d
Departments of aBehavioral Sciences, bNeurological Sciences and cInternal Medicine, and dRush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Ill., USA
email Corresponding Author

Abstract

Background: The apolipoprotein E (APOE) ε4 allele is a well-known risk factor for the development of Alzheimer’s disease, but little is known about the association of the ε4 allele with incident mild cognitive impairment (MCI). Objective: Test the hypothesis that the ε4 allele is associated with an increased risk of developing MCI. Methods: More than 600 older Catholic clergy members from the Religious Orders Study without any cognitive impairment at baseline underwent APOE genotyping and detailed annual clinical evaluations for up to 16 years of follow-up (mean: 10.17 years; range: 2–16 years) to document incident MCI and rates of decline in global cognition and 5 cognitive domains (i.e. episodic memory, semantic memory, working memory, perceptual speed and visuospatial abilities). Results: During up to 16 years of annual follow-up, 339 of 607 persons (56%) developed MCI. In a proportional hazards model adjusted for age, sex and education, the presence of the APOE ε4 allele was associated with a 1.4-fold increased risk of incident MCI (hazard ratio: 1.36; 95% CI: 1.04, 1.78). Further, this association persisted in analyses that required MCI to persist for at least one year (hazard ratio: 1.50; 95% CI: 1.05, 2.14). Finally, the ε4 allele was associated with an increased rate of decline in global cognition and 4 out of 5 cognitive systems (i.e. episodic memory, semantic memory, working memory and perceptual speed). Conclusion: The presence of the APOE ε4 allele is associated with an increased risk of MCI and a more rapid rate of cognitive decline in old age.

© 2009 S. Karger AG, Basel


  

Key Words

  • Apolipoprotein E
  • Mild cognitive impairment
  • Aging
  • Alzheimer’s disease, preclinical

References

  1. Schneider JA, Arvanitakis Z, Bang W, Bennett DA: Mixed pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007;69:2197–2204.
  2. Schneider JA, Bienias JL, Wilson RS, Berry-Kravis E, Evans DA, Bennett DA: The apolipoprotein E ε4 allele increases the odds of chronic cerebral infarction detected at autopsy in older persons. Stroke 2005;36:954–959.
  3. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, Cochran EJ, Berry-Kravis E, Bienias JL: Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 2003;60:246–252.
  4. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Berry-Kravis E, Arnold SE: Amyloid mediates the association of apolipoprotein E ε4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry 2005;76:1194–1199.
  5. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB: Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 2008;148:427–434.
  6. 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 ε4 allele. Neurology 2004;62:1990–1995.
  7. Tervo S, Kivipelto M, Hänninen T, Vanhanen M, Hallikainen M, Mannermaa A, Soininen H: Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects. Dement Geriatr Cogn Disord 2004;17:196–203.
  8. SAS 9.1.3 Help and Documentation. Cary, SAS Institute Inc., 2000.
  9. Laird N, Waire J: Random effects models for longitudinal data. Biometrics 1982;38:963–974.
  10. Cox DR: Regression models and life tables. J R Stat Soc Ser B Methodol 1972;34:187–220.
  11. Buchman AS, Boyle PA, Wilson RS, Beck TL, Kelly JF, Bennett DA: Apolipoprotein E ε4 allele is associated with more rapid motor decline in older persons. Alzheimer Dis Assoc Disord 2009;23:63–69.
  12. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA: Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease. Arch Neurol 2006;63:1763–1769.
  13. Tuokko H, Frerichs R, Graham J, Rockwood K, Kristjansson B, Fisk J, Bergman H, Kozma A, McDowell I: Five-year follow-up of cognitive impairment with no dementia. Arch Neurol 2003;60:577–582.
  14. 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.
  15. Folstein M, Folstein S, McHugh P: Mini-Mental State: a practical method for grading the mental state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  16. Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, Woodruff BK, Alexander GE, Osborne D: Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol 2007;64:1306–1311.
  17. Tyas SL, Salazar JC, Snowdon DA, Desrosiers MF, Riley KP, Mendiondo MS, Kryscio RJ: Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol 2007;165:1231–1238.
  18. Kryscio RJ, Schmitt FA, Salazar JC, Mendiondo MS, Markesbery WR: Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66:828–832.
  19. Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, Jolles J, Verhey FR: The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement Geriatr Cogn Disord 2008;26:101–108.
  20. Mosconi L, Perani D, Sorbi S, Herholz K, Nacmias B, Holthoff V, Salmon E, Baron JC, de Cristofaro MT, Padovani A, Borroni B, Franceschi M, Bracco L, Pupi A: MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET. Neurology 2004;63:2332–2340.
  21. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Berry-Kravis E, Bennett DA: The apolipoprotein E ε4 allele and incident Alzheimer’s disease in persons with mild cognitive impairment. Neurocase 2005;11:3–7.
  22. Wilson RS, Schneider JA, Barnes LL, Beckett LA, Aggarwal NT, Cochran EJ, Berry-Kravis E, Bach J, Fox JH, Evans DA, Bennett DA: The apolipoprotein E ε4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol 2002;59:1154–1160.
  23. Evans DA, Beckett LA, Field TS, Feng L, Albert MS, Bennett DA, Tycko B, Mayeux R: Apolipoprotein E ε4 and incidence of Alzheimer disease in a community population of older persons. JAMA 1997;277:822–824.
  24. 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.
  25. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, Cochran EJ, Berry-Kravis E, Bienias JL: Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 2003;60:246–252.
  26. Evans DA, Bennett DA, Wilson RS, Bienias JL, Morris MC, Scherr PA, Hebert LE, Aggarwal N, Beckett LA, Joglekar R, Berry-Kravis E, Schneider J: Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol 2003;60:185–189.
  27. Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA: Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007;64:802–808.
  28. Wilson RS, Schneider JA, Arnold SE, Bienias JL, Bennett DA: Conscientiousness and the incidence of Alzheimer disease and mild cognitive impairment. Arch Gen Psychiatry 2007;64:1204–1212.
  29. Geda YE, Knopman DS, Mrazek DA, Jicha GA, Smith GE, Negash S, Boeve BF, Ivnik RJ, Petersen RC, Pankratz VS, Rocca WA: Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study. Arch Neurol 2006;63:435–440.
  30. Solfrizzi V, Panza F, Colacicco AM, D’Introno A, Capurso C, Torres F, Grigoletto F, Maggi S, del Parigi A, Reiman EM, Caselli RJ, Scafato E, Farchi G, Capurso A, Italian Longitudinal Study on Aging Working Group: Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004;63:1882–1891.
  31. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA: Hypertension and the risk of mild cognitive impairment. Arch Neurol 2007;64:1734–1740.
  32. Riley KP, Snowdon DA, Markesbery WR: Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 2002;51:567–577.
  33. Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR: Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006;63:38–46.
  34. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS: Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66:1837–1844.
  35. Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS: Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005;64:834–841.
  36. Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA: Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006;67:441–445.
  37. Bennett DA, Wilson RS, Schneider JA, et al: Natural history of mild cognitive impairment in older persons. Neurology 2002;59:198–205.
  38. Morris JC: Mild cognitive impairment is early-stage Alzheimer disease. Arch Neurol 2006;63:15–16.
  39. Fisk JD, Merry HR, Rockwood K: Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology 2003;61:1179–1184.
  40. Larrieu S, Letenneur L, Orgogozo JM, et al: Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 2002;59:1594–1599.

  

Author Contacts

Patricia Boyle, PhD
Rush Alzheimer’s Disease Center, Rush University Medical Center
Armour Academic Facility, Suite 1020B
600 South Paulina Street, Chicago, IL 60612 (USA)
Tel. +1 312 942 8749, Fax +1 312 563 4604, E-Mail Patricia_Boyle@rush.edu

  

Article Information

Received: May 17, 2009
Accepted: September 7, 2009
Published online: November 11, 2009
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 2, Number of References : 40

  

Publication Details

Neuroepidemiology

Vol. 34, No. 1, Year 2010 (Cover Date: January 2010)

Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251-5350 (Print), eISSN: 1423-0208 (Online)

For additional information: http://www.karger.com/NED


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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

Abstract

Background: The apolipoprotein E (APOE) ε4 allele is a well-known risk factor for the development of Alzheimer’s disease, but little is known about the association of the ε4 allele with incident mild cognitive impairment (MCI). Objective: Test the hypothesis that the ε4 allele is associated with an increased risk of developing MCI. Methods: More than 600 older Catholic clergy members from the Religious Orders Study without any cognitive impairment at baseline underwent APOE genotyping and detailed annual clinical evaluations for up to 16 years of follow-up (mean: 10.17 years; range: 2–16 years) to document incident MCI and rates of decline in global cognition and 5 cognitive domains (i.e. episodic memory, semantic memory, working memory, perceptual speed and visuospatial abilities). Results: During up to 16 years of annual follow-up, 339 of 607 persons (56%) developed MCI. In a proportional hazards model adjusted for age, sex and education, the presence of the APOE ε4 allele was associated with a 1.4-fold increased risk of incident MCI (hazard ratio: 1.36; 95% CI: 1.04, 1.78). Further, this association persisted in analyses that required MCI to persist for at least one year (hazard ratio: 1.50; 95% CI: 1.05, 2.14). Finally, the ε4 allele was associated with an increased rate of decline in global cognition and 4 out of 5 cognitive systems (i.e. episodic memory, semantic memory, working memory and perceptual speed). Conclusion: The presence of the APOE ε4 allele is associated with an increased risk of MCI and a more rapid rate of cognitive decline in old age.

© 2009 S. Karger AG, Basel


  

Author Contacts

Patricia Boyle, PhD
Rush Alzheimer’s Disease Center, Rush University Medical Center
Armour Academic Facility, Suite 1020B
600 South Paulina Street, Chicago, IL 60612 (USA)
Tel. +1 312 942 8749, Fax +1 312 563 4604, E-Mail Patricia_Boyle@rush.edu

  

Article Information

Received: May 17, 2009
Accepted: September 7, 2009
Published online: November 11, 2009
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 2, Number of References : 40

  

Publication Details

Neuroepidemiology

Vol. 34, No. 1, Year 2010 (Cover Date: January 2010)

Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251-5350 (Print), eISSN: 1423-0208 (Online)

For additional information: http://www.karger.com/NED


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 5/17/2009
Accepted: 9/7/2009
Published online: 11/11/2009
Issue release date: January 2010

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 2

ISSN: 0251-5350 (Print)
eISSN: 1423-0208 (Online)

For additional information: http://www.karger.com/NED


Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Schneider JA, Arvanitakis Z, Bang W, Bennett DA: Mixed pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007;69:2197–2204.
  2. Schneider JA, Bienias JL, Wilson RS, Berry-Kravis E, Evans DA, Bennett DA: The apolipoprotein E ε4 allele increases the odds of chronic cerebral infarction detected at autopsy in older persons. Stroke 2005;36:954–959.
  3. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, Cochran EJ, Berry-Kravis E, Bienias JL: Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 2003;60:246–252.
  4. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Berry-Kravis E, Arnold SE: Amyloid mediates the association of apolipoprotein E ε4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry 2005;76:1194–1199.
  5. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB: Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 2008;148:427–434.
  6. 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 ε4 allele. Neurology 2004;62:1990–1995.
  7. Tervo S, Kivipelto M, Hänninen T, Vanhanen M, Hallikainen M, Mannermaa A, Soininen H: Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects. Dement Geriatr Cogn Disord 2004;17:196–203.
  8. SAS 9.1.3 Help and Documentation. Cary, SAS Institute Inc., 2000.
  9. Laird N, Waire J: Random effects models for longitudinal data. Biometrics 1982;38:963–974.
  10. Cox DR: Regression models and life tables. J R Stat Soc Ser B Methodol 1972;34:187–220.
  11. Buchman AS, Boyle PA, Wilson RS, Beck TL, Kelly JF, Bennett DA: Apolipoprotein E ε4 allele is associated with more rapid motor decline in older persons. Alzheimer Dis Assoc Disord 2009;23:63–69.
  12. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA: Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease. Arch Neurol 2006;63:1763–1769.
  13. Tuokko H, Frerichs R, Graham J, Rockwood K, Kristjansson B, Fisk J, Bergman H, Kozma A, McDowell I: Five-year follow-up of cognitive impairment with no dementia. Arch Neurol 2003;60:577–582.
  14. 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.
  15. Folstein M, Folstein S, McHugh P: Mini-Mental State: a practical method for grading the mental state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  16. Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, Woodruff BK, Alexander GE, Osborne D: Cognitive domain decline in healthy apolipoprotein E ε4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol 2007;64:1306–1311.
  17. Tyas SL, Salazar JC, Snowdon DA, Desrosiers MF, Riley KP, Mendiondo MS, Kryscio RJ: Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol 2007;165:1231–1238.
  18. Kryscio RJ, Schmitt FA, Salazar JC, Mendiondo MS, Markesbery WR: Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66:828–832.
  19. Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, Jolles J, Verhey FR: The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement Geriatr Cogn Disord 2008;26:101–108.
  20. Mosconi L, Perani D, Sorbi S, Herholz K, Nacmias B, Holthoff V, Salmon E, Baron JC, de Cristofaro MT, Padovani A, Borroni B, Franceschi M, Bracco L, Pupi A: MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET. Neurology 2004;63:2332–2340.
  21. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Berry-Kravis E, Bennett DA: The apolipoprotein E ε4 allele and incident Alzheimer’s disease in persons with mild cognitive impairment. Neurocase 2005;11:3–7.
  22. Wilson RS, Schneider JA, Barnes LL, Beckett LA, Aggarwal NT, Cochran EJ, Berry-Kravis E, Bach J, Fox JH, Evans DA, Bennett DA: The apolipoprotein E ε4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol 2002;59:1154–1160.
  23. Evans DA, Beckett LA, Field TS, Feng L, Albert MS, Bennett DA, Tycko B, Mayeux R: Apolipoprotein E ε4 and incidence of Alzheimer disease in a community population of older persons. JAMA 1997;277:822–824.
  24. 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.
  25. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, Cochran EJ, Berry-Kravis E, Bienias JL: Apolipoprotein E ε4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 2003;60:246–252.
  26. Evans DA, Bennett DA, Wilson RS, Bienias JL, Morris MC, Scherr PA, Hebert LE, Aggarwal N, Beckett LA, Joglekar R, Berry-Kravis E, Schneider J: Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol 2003;60:185–189.
  27. Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA: Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007;64:802–808.
  28. Wilson RS, Schneider JA, Arnold SE, Bienias JL, Bennett DA: Conscientiousness and the incidence of Alzheimer disease and mild cognitive impairment. Arch Gen Psychiatry 2007;64:1204–1212.
  29. Geda YE, Knopman DS, Mrazek DA, Jicha GA, Smith GE, Negash S, Boeve BF, Ivnik RJ, Petersen RC, Pankratz VS, Rocca WA: Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study. Arch Neurol 2006;63:435–440.
  30. Solfrizzi V, Panza F, Colacicco AM, D’Introno A, Capurso C, Torres F, Grigoletto F, Maggi S, del Parigi A, Reiman EM, Caselli RJ, Scafato E, Farchi G, Capurso A, Italian Longitudinal Study on Aging Working Group: Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004;63:1882–1891.
  31. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA: Hypertension and the risk of mild cognitive impairment. Arch Neurol 2007;64:1734–1740.
  32. Riley KP, Snowdon DA, Markesbery WR: Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 2002;51:567–577.
  33. Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR: Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006;63:38–46.
  34. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS: Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66:1837–1844.
  35. Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS: Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005;64:834–841.
  36. Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA: Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006;67:441–445.
  37. Bennett DA, Wilson RS, Schneider JA, et al: Natural history of mild cognitive impairment in older persons. Neurology 2002;59:198–205.
  38. Morris JC: Mild cognitive impairment is early-stage Alzheimer disease. Arch Neurol 2006;63:15–16.
  39. Fisk JD, Merry HR, Rockwood K: Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology 2003;61:1179–1184.
  40. Larrieu S, Letenneur L, Orgogozo JM, et al: Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 2002;59:1594–1599.