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Table of Contents
Vol. 34, No. 4, 2010
Issue release date: May 2010
Free Access
Neuroepidemiology 2010;34:200–207
(DOI:10.1159/000289351)

Fasting Plasma Insulin, C-Peptide and Cognitive Change in Older Men without Diabetes: Results from the Physicians’ Health Study II

Okereke O.I.a, c · Kurth T.a, b, d, g, h · Pollak M.N.f · Gaziano J.M.a, b, e · Grodstein F.a, c, d
Divisions of aAging and bPreventive Medicine, and cChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, and dDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass., and eVA Boston Healthcare System, Jamaica Plain, Mass., USA; fDepartments of Medicine and Oncology, Lady Davis Research Institute of the Jewish General Hospital and McGill University, Montreal, Que., Canada; gINSERM U708 and hUniversité Pierre et Marie Curie, Paris, France
email Corresponding Author

Abstract

Background: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes. Methods: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline. Results: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was –0.62 (–1.15, –0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03). Conclusions: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.


 goto top of outline Key Words

  • Insulin
  • C-Peptide
  • Cognitive decline
  • Dementia
  • Diabetes

 goto top of outline Abstract

Background: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes. Methods: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline. Results: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was –0.62 (–1.15, –0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03). Conclusions: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Coker LH, Shumaker SA: Type 2 diabetes mellitus and cognition: an understudied issue in women’s health. J Psychosom Res 2003;54:129–139.
  2. Legato MJ, Gelzer A, Goland R, Ebner SA, Rajan S, Villagra V, Kosowski M, Writing Group for the Partnership for Gender-Specific Medicine: Gender-specific care of the patient with diabetes: review and recommendations. Gend Med 2006;3:131–158.
  3. Avogaro A, Giorda C, Maggini M, Mannucci E, Raschetti R, Lombardo F, Spila-Alegiani S, Turco S, Velussi M, Ferrannini E, Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità: Incidence of coronary heart disease in type-2-diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care 2007;30:1241–1247.
  4. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM: Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2008;300:2123–2133.
  5. Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Sesso HD, Buring JE: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2009;301:52–62.
  6. Steering Committee of the Physicians’ Health Study Research Group: Preliminary report: findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988;318:262–264.
  7. Steering Committee of the Physicians’ Health Study Research Group: Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321:129–135.
  8. Djoussé L, Kurth T, Gaziano JM: Cystatin C and risk of heart failure in the Physicians’ Health Study (PHS). Am Heart J 2008;155:82–86.
  9. Chen BH, Song Y, Ding EL, Roberts CK, Manson JE, Rifai N, Buring JE, Gaziano JM, Liu S: Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts. Diabetes Care 2009;32:329–334.
  10. Faber OK, Binder C, Markussen J, Heding LG, Naithani VK, Kuzuya H, Blix P, Horwitz DL, Rubenstein AH: Characterization of seven C-peptide antisera. Diabetes 1978;27:170–177.
  11. Okereke OI, Kang JH, Cook NR, Gaziano JM, Manson JE, Buring JE, Grodstein F: Type 2 diabetes and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 2008;56:1028–1036.
  12. Brandt J, Spencer M, Folstein M: The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:111–117.
  13. 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.
  14. Albert M, Smith LA, Scherr PA, Taylor JO, Evans DA, Funkenstein HH: Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57:167–178.
  15. Royall DR, Lauterbach EC, Cummings JL, Reeve A, Rummans TA, Kaufer DI, LaFrance WC Jr, Coffey CE: Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 2002;14:377–405.
  16. Kang JH, Cook N, Manson J, Buring JE, Grodstein F: A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 2006;166:2462–2468.
  17. Ajani UA, Gaziano JM, Lotufo PA, Liu S, Hennekens CH, Buring JE, Manson JE: Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation 2000;102:500–505.
  18. Cho E, Rimm EB, Stampfer MJ, Willett WC, Hu FB: The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men. J Am Coll Cardiol 2002;40:954–956.
  19. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L: The course of cognitive impairment in preclinical Alzheimer disease: three- and six-year follow-up of a population-based sample. Arch Neurol 2000;57:839–844.
  20. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853–858.
  21. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–1222.
  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 epsilon 4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol 2002;59:1154–1160.
  23. Román GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, López-Pousa S, Arizaga R, Wallin A: Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004;226:81–87.
  24. Okereke O, Kang JH, Gaziano JM, Ma J, Stampfer MJ, Grodstein F: Plasma C-peptide and cognitive performance in older men without diabetes. Am J Geriatr Psychiatry 2006;14:1041–1050.
  25. Peila R, Rodriguez BL, White LR, Launer LJ: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004;63:228–233.
  26. Kalmijn S, Feskens EJM, Launer LJ, Stijnen T, Kromhout D: Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38:1096–1102.
  27. Stolk RP, Breteler MMB, Ott A, Pols HA, Lamberts SW, Grobbee DE, Hofman A: Insulin and cognitive function in an elderly population: the Rotterdam study. Diabetes Care 1997;20:792–795.
  28. Abbatecola AM, Paolisso G, Lamponi M, Bandinelli S, Lauretani F, Launer L, Ferrucci L: Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc 2004;52:1713–1718.
  29. Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM, Zanetti O, Guralnik JM, Ferrucci L: Insulin resistance in cognitive impairment: the InCHIANTI Study. Arch Neurol 2005;62:1067–1072.
  30. Okereke O, Hankinson SE, Hu FB, Grodstein F: Plasma C-peptide and cognitive function among older women without diabetes. Arch Intern Med 2005;165:1651–1656.
  31. Luchsinger J, Tang M-X, Shea S, Mayeux R: Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187–1192.
  32. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63:658–663.
  33. Okereke OI, Pollak MN, Hu FB, Hankinson SE, Selkoe DJ, Grodstein F: Plasma C-peptide levels and rates of cognitive decline in older, community-dwelling women without diabetes. Psychoneuroendocrinology 2008;33:455–461.
  34. van Oijen M, Okereke OI, Kang JH, Pollak MN, Hu FB, Hankinson SE, Grodstein F: Fasting insulin levels and cognitive decline in older women without diabetes. Neuroepidemiology 2008;30:174–179.
  35. Katzman R, Brown T, Fuld P, Peck A, Schechter R, Schimmel H: Validation of a short orientation-memory-concentration test of cognitive impairment. Am J Psychiatry 1983;140:734–739.
  36. Hsueh WA, Quinones MJ: Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92:10J–17J.
  37. Duckworth WC, Bennett RG, Hamel FG: Insulin degradation: progress and potential. Endocr Rev 1998;19:608–624.
  38. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM: Brain-to-plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002;295:2264–2267.
  39. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S: Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005;62:1539–1544.
  40. Craft S: Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 2005;26:65–69.
  41. Zhao WQ, Alkon DL: Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001;177:125–134.
  42. Manson JE, Stampfer MJ, Colditz GA, Willett WC, Rosner B, Hennekens CH, Speizer FE, Rimm EB, Krolewski AS: Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338:774–778.
  43. Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ: A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 2004;96:546–553.

 goto top of outline Author Contacts

Dr. Olivia Okereke
Channing Laboratory 3rd floor
181 Longwood Avenue
Boston, MA 02115 (USA)
Tel. +1 617 525 2027, Fax +1 617 525 2008, E-Mail ookereke@partners.org


 goto top of outline Article Information

Received: September 14, 2009
Accepted: November 23, 2009
Published online: March 3, 2010
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 2, Number of References : 43


 goto top of outline Publication Details

Neuroepidemiology

Vol. 34, No. 4, Year 2010 (Cover Date: May 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: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes. Methods: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline. Results: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was –0.62 (–1.15, –0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03). Conclusions: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.



 goto top of outline Author Contacts

Dr. Olivia Okereke
Channing Laboratory 3rd floor
181 Longwood Avenue
Boston, MA 02115 (USA)
Tel. +1 617 525 2027, Fax +1 617 525 2008, E-Mail ookereke@partners.org


 goto top of outline Article Information

Received: September 14, 2009
Accepted: November 23, 2009
Published online: March 3, 2010
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 2, Number of References : 43


 goto top of outline Publication Details

Neuroepidemiology

Vol. 34, No. 4, Year 2010 (Cover Date: May 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

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. Coker LH, Shumaker SA: Type 2 diabetes mellitus and cognition: an understudied issue in women’s health. J Psychosom Res 2003;54:129–139.
  2. Legato MJ, Gelzer A, Goland R, Ebner SA, Rajan S, Villagra V, Kosowski M, Writing Group for the Partnership for Gender-Specific Medicine: Gender-specific care of the patient with diabetes: review and recommendations. Gend Med 2006;3:131–158.
  3. Avogaro A, Giorda C, Maggini M, Mannucci E, Raschetti R, Lombardo F, Spila-Alegiani S, Turco S, Velussi M, Ferrannini E, Diabetes and Informatics Study Group, Association of Clinical Diabetologists, Istituto Superiore di Sanità: Incidence of coronary heart disease in type-2-diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care 2007;30:1241–1247.
  4. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM: Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2008;300:2123–2133.
  5. Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Sesso HD, Buring JE: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2009;301:52–62.
  6. Steering Committee of the Physicians’ Health Study Research Group: Preliminary report: findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988;318:262–264.
  7. Steering Committee of the Physicians’ Health Study Research Group: Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321:129–135.
  8. Djoussé L, Kurth T, Gaziano JM: Cystatin C and risk of heart failure in the Physicians’ Health Study (PHS). Am Heart J 2008;155:82–86.
  9. Chen BH, Song Y, Ding EL, Roberts CK, Manson JE, Rifai N, Buring JE, Gaziano JM, Liu S: Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts. Diabetes Care 2009;32:329–334.
  10. Faber OK, Binder C, Markussen J, Heding LG, Naithani VK, Kuzuya H, Blix P, Horwitz DL, Rubenstein AH: Characterization of seven C-peptide antisera. Diabetes 1978;27:170–177.
  11. Okereke OI, Kang JH, Cook NR, Gaziano JM, Manson JE, Buring JE, Grodstein F: Type 2 diabetes and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 2008;56:1028–1036.
  12. Brandt J, Spencer M, Folstein M: The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:111–117.
  13. 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.
  14. Albert M, Smith LA, Scherr PA, Taylor JO, Evans DA, Funkenstein HH: Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57:167–178.
  15. Royall DR, Lauterbach EC, Cummings JL, Reeve A, Rummans TA, Kaufer DI, LaFrance WC Jr, Coffey CE: Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 2002;14:377–405.
  16. Kang JH, Cook N, Manson J, Buring JE, Grodstein F: A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 2006;166:2462–2468.
  17. Ajani UA, Gaziano JM, Lotufo PA, Liu S, Hennekens CH, Buring JE, Manson JE: Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation 2000;102:500–505.
  18. Cho E, Rimm EB, Stampfer MJ, Willett WC, Hu FB: The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men. J Am Coll Cardiol 2002;40:954–956.
  19. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L: The course of cognitive impairment in preclinical Alzheimer disease: three- and six-year follow-up of a population-based sample. Arch Neurol 2000;57:839–844.
  20. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853–858.
  21. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–1222.
  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 epsilon 4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol 2002;59:1154–1160.
  23. Román GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, López-Pousa S, Arizaga R, Wallin A: Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004;226:81–87.
  24. Okereke O, Kang JH, Gaziano JM, Ma J, Stampfer MJ, Grodstein F: Plasma C-peptide and cognitive performance in older men without diabetes. Am J Geriatr Psychiatry 2006;14:1041–1050.
  25. Peila R, Rodriguez BL, White LR, Launer LJ: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004;63:228–233.
  26. Kalmijn S, Feskens EJM, Launer LJ, Stijnen T, Kromhout D: Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38:1096–1102.
  27. Stolk RP, Breteler MMB, Ott A, Pols HA, Lamberts SW, Grobbee DE, Hofman A: Insulin and cognitive function in an elderly population: the Rotterdam study. Diabetes Care 1997;20:792–795.
  28. Abbatecola AM, Paolisso G, Lamponi M, Bandinelli S, Lauretani F, Launer L, Ferrucci L: Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc 2004;52:1713–1718.
  29. Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM, Zanetti O, Guralnik JM, Ferrucci L: Insulin resistance in cognitive impairment: the InCHIANTI Study. Arch Neurol 2005;62:1067–1072.
  30. Okereke O, Hankinson SE, Hu FB, Grodstein F: Plasma C-peptide and cognitive function among older women without diabetes. Arch Intern Med 2005;165:1651–1656.
  31. Luchsinger J, Tang M-X, Shea S, Mayeux R: Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187–1192.
  32. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63:658–663.
  33. Okereke OI, Pollak MN, Hu FB, Hankinson SE, Selkoe DJ, Grodstein F: Plasma C-peptide levels and rates of cognitive decline in older, community-dwelling women without diabetes. Psychoneuroendocrinology 2008;33:455–461.
  34. van Oijen M, Okereke OI, Kang JH, Pollak MN, Hu FB, Hankinson SE, Grodstein F: Fasting insulin levels and cognitive decline in older women without diabetes. Neuroepidemiology 2008;30:174–179.
  35. Katzman R, Brown T, Fuld P, Peck A, Schechter R, Schimmel H: Validation of a short orientation-memory-concentration test of cognitive impairment. Am J Psychiatry 1983;140:734–739.
  36. Hsueh WA, Quinones MJ: Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92:10J–17J.
  37. Duckworth WC, Bennett RG, Hamel FG: Insulin degradation: progress and potential. Endocr Rev 1998;19:608–624.
  38. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM: Brain-to-plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002;295:2264–2267.
  39. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S: Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005;62:1539–1544.
  40. Craft S: Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 2005;26:65–69.
  41. Zhao WQ, Alkon DL: Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001;177:125–134.
  42. Manson JE, Stampfer MJ, Colditz GA, Willett WC, Rosner B, Hennekens CH, Speizer FE, Rimm EB, Krolewski AS: Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338:774–778.
  43. Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ: A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 2004;96:546–553.