Skip to main content

Advertisement

Log in

Diabetes Mellitus and Dementia

  • Diabetes and Other Diseases-Emerging Associations (JJ Nolan, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Growing epidemiologic evidence has suggested that people with diabetes mellitus are at an increased risk for the development of dementia. However, the results for the subtypes of dementia are inconsistent. This review examines the risk of dementia in people with diabetes mellitus, and discusses the possible mechanism underpinning this association. Diabetes mellitus is associated with a 1.5- to 2.5-fold greater risk of dementia among community-dwelling elderly people. Notably, diabetes mellitus is a significant risk factor for not only vascular dementia, but also Alzheimer’s disease. The mechanisms underpinning the association are unclear, but it may be multifactorial in nature, involving factors such as cardiovascular risk factors, glucose toxicity, changes in insulin metabolism and inflammation. The optimal management of these risk factors in early life may be important to prevent late-life dementia. Furthermore, novel therapeutic strategies will be needed to prevent or reduce the development of dementia in people with diabetes mellitus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. World Health Organization and Alzheimer’s Disease International. Dementia. A public health priority. Available at: http://www.who.int/mental_health/publications/dementia_report_2012/en/. Accessed 18 Aug 2013.

  2. World health organization. World health report 2003-shaping the future. Geneva: WHO. 2003.

  3. The IDF Diabetes Atlas, 5th edition. Available at: http://www.Idf.Org/diabetesatlas/5e/diabetes. Accessed 26 Jul 2013.

  4. Lu FP, Lin KP, Kuo HK. Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PloS One. 2009;4:e4144. This study provides the comprehensive information about the influence of diabetes mellitus on the risk of geriatric health complications.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5:64–74.

    Article  PubMed  Google Scholar 

  6. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol. 2009;66:200–8.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Matsui Y, Tanizaki Y, Arima H, Yonemoto K, Doi Y, Ninomiya T, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama Study. J Neurol Neurosurg Psychiatry. 2009;80:366–70.

    Article  PubMed  CAS  Google Scholar 

  8. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145:301–8.

    Article  PubMed  CAS  Google Scholar 

  9. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53:1937–42.

    Article  PubMed  CAS  Google Scholar 

  10. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol. 2001;154:635–41.

    Article  PubMed  CAS  Google Scholar 

  11. MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord. 2002;14:77–83.

    Article  PubMed  Google Scholar 

  12. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes. 2002;51:1256–62.

    Article  PubMed  CAS  Google Scholar 

  13. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661–6.

    Article  PubMed  Google Scholar 

  14. Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol. 2006;63:1551–5.

    Article  PubMed  Google Scholar 

  15. Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and ApoE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol. 2008;65:89–93.

    Article  PubMed  Google Scholar 

  16. Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C, et al. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-city Study. Diabetes Care. 2009;32:169–74.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Alonso A, Mosley Jr TH, Gottesman RF, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk In Communities (ARIC) Study. J Neurol Neurosurg Psychiatry. 2009;80:1194–201.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Ronnemaa E, Zethelius B, Sundelof J, Sundstrom J, Degerman-Gunnarsson M, Lannfelt L, et al. Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12-year follow-up study in 71-year-old men. Diabetologia. 2009;52:1504–10.

    Article  PubMed  CAS  Google Scholar 

  19. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia. 2009;52:1031–9.

    Article  PubMed  CAS  Google Scholar 

  20. Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology. 2010;75:1195–202.

    Article  PubMed  CAS  Google Scholar 

  21. Mejia-Arango S. Zuniga-Gil C [diabetes mellitus as a risk factor for dementia in the Mexican elder population]. Rev Neurol. 2011;53:397–405.

    PubMed  Google Scholar 

  22. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama Study. Neurology. 2011;77:1126–34. This study provides the reliable findings of the relationship between diabetes-related factors and dementia, because the diabetes status and outcomes were ascertained precisely.

    Article  PubMed  CAS  Google Scholar 

  23. Cheng D, Noble J, Tang MX, Schupf N, Mayeux R, Luchsinger JA. Type 2 diabetes and late-onset Alzheimer's disease. Dement Geriatr Cogn Disord. 2011;31:424–30.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Hassing LB, Johansson B, Nilsson SE, Berg S, Pedersen NL, Gatz M, et al. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's disease: a population-based study of the oldest old. Int Psychogeriatr. 2002;14:239–48.

    Article  PubMed  Google Scholar 

  25. Hayden KM, Zandi PP, Lyketsos CG, Khachaturian AS, Bastian LA, Charoonruk G, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache county Study. Alzheimer Dis Assoc Disord. 2006;20:93–100.

    Article  PubMed  Google Scholar 

  26. Thacker EL, Psaty BM, McKnight B, Heckbert SR, Longstreth Jr WT, Mukamal KJ, et al. Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. Stroke. 2011;42:3347–51.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Doi Y, Ninomiya T, Hata J, Fukuhara M, Yonemoto K, Iwase M, et al. Impact of glucose tolerance status on development of ischemic stroke and coronary heart disease in a general Japanese population: the Hisayama Study. Stroke. 2010;41:203–9.

    Article  PubMed  CAS  Google Scholar 

  28. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    Article  PubMed  CAS  Google Scholar 

  29. Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA. Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology. 2002;58:1476–82.

    Article  PubMed  CAS  Google Scholar 

  30. Convit A, De Leon MJ, Tarshish C, De Santi S, Tsui W, Rusinek H, et al. Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease. Neurobiol Aging. 1997;18:131–8.

    Article  PubMed  CAS  Google Scholar 

  31. Schott JM, Fox NC, Frost C, Scahill RI, Janssen JC, Chan D, et al. Assessing the onset of structural change in familial Alzheimer's disease. Ann Neurol. 2003;53:181–8.

    Article  PubMed  Google Scholar 

  32. Krasuski JS, Alexander GE, Horwitz B, Daly EM, Murphy DG, Rapoport SI, et al. Volumes of medial temporal lobe structures in patients with Alzheimer's disease and mild cognitive impairment (and in healthy controls). Biol Psychiatry. 1998;43:60–8.

    Article  PubMed  CAS  Google Scholar 

  33. den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia. 2003;46:1604–10.

    Article  Google Scholar 

  34. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama Study. Neurology. 2010;75:764–70.

    Article  PubMed  CAS  Google Scholar 

  35. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS Autopsy Study. Neurology. 2002;58:1629–34.

    Article  PubMed  CAS  Google Scholar 

  36. Mankovsky BN, Ziegler D. Stroke in patients with diabetes mellitus. Diabetes Metab Res Rev. 2004;20:268–87.

    Article  PubMed  Google Scholar 

  37. Kalmijn S, Foley D, White L, Burchfiel CM, Curb JD, Petrovitch H, et al. Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. the Honolulu-Asia Aging Study. Arterioscler Thromb Vasc Biol. 2000;20:2255–60.

    Article  PubMed  CAS  Google Scholar 

  38. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005;64:277–81.

    Article  PubMed  CAS  Google Scholar 

  39. Serlin Y, Levy J, Shalev H. Vascular pathology and blood-brain barrier disruption in cognitive and psychiatric complications of type 2 diabetes mellitus. Cardiovasc Psychiatry Neurol. 2011;2011:609202.

    Article  PubMed Central  PubMed  Google Scholar 

  40. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst Rev. 2009:CD004034.

  41. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163:1069–75.

    Article  PubMed  CAS  Google Scholar 

  42. McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2009;2, CD003160.

    PubMed  Google Scholar 

  43. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4:487–99.

    Article  PubMed  Google Scholar 

  44. Ninomiya T, Ohara T, Hirakawa Y, Yoshida D, Doi Y, Hata J, et al. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama Study. Hypertension. 2011;58:22–8.

    Article  PubMed  CAS  Google Scholar 

  45. Sommerfield AJ, Deary IJ, Frier BM. Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care. 2004;27:2335–40.

    Article  PubMed  Google Scholar 

  46. Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, Waberski B, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007;356:1842–52.

    Article  PubMed  Google Scholar 

  47. Biessels GJ, Kamal A, Ramakers GM, Urban IJ, Spruijt BM, Erkelens DW, et al. Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes. 1996;45:1259–66.

    Article  PubMed  CAS  Google Scholar 

  48. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.

    Article  PubMed  CAS  Google Scholar 

  49. Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (accord mind): a randomized open-label substudy. Lancet Neurol. 2011;10:969–77. This study is a randomized control trial addressing the treatment effect of the tight glucose control on the cognitive function and the morphologic changes of the brain.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Whitmer RA, Karter AJ, Yaffe K, Quesenberry Jr CP, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301:1565–72.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Lin CH, Sheu WH. Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med. 2013;273:102–10.

    Article  PubMed  Google Scholar 

  52. de Galan BE, Zoungas S, Chalmers J, Anderson C, Dufouil C, Pillai A, et al. ADVANCE Collaborative Group. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia. 2009;52:2328–36.

    Article  PubMed  CAS  Google Scholar 

  53. Fanelli CG, Porcellati F, Pampanelli S, Bolli GB. Insulin therapy and hypoglycaemia: the size of the problem. Diabetes Metab Res Rev. 2004;20 Suppl 2:S32–42.

    Article  PubMed  CAS  Google Scholar 

  54. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev. 2008;24:353–63.

    Article  PubMed  CAS  Google Scholar 

  55. Artola A, Kamal A, Ramakers GM, Gardoni F, Di Luca M, Biessels GJ, et al. Synaptic plasticity in the diabetic brain: advanced aging? Prog Brain Res. 2002;138:305–14.

    Article  PubMed  CAS  Google Scholar 

  56. Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci. 2000;23:542–9.

    Article  PubMed  CAS  Google Scholar 

  57. Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001;177:125–34.

    Article  PubMed  CAS  Google Scholar 

  58. Zemva J, Schubert M. Central insulin and insulin-like growth factor-1 signaling: implications for diabetes associated dementia. Curr Diabetes Rev. 2011;7:356–66.

    Article  PubMed  CAS  Google Scholar 

  59. Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer S. Modeling sporadic Alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities including hyperphosphorylated tau protein and amyloid-beta. J Alzheimers Dis. 2009;18:729–50.

    PubMed  CAS  Google Scholar 

  60. Neumann KF, Rojo L, Navarrete LP, Farias G, Reyes P, Maccioni RB. Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr Alzheimer Res. 2008;5:438–47.

    Article  PubMed  CAS  Google Scholar 

  61. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte Jr D. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein e genotype. Neurology. 1998;50:164–8.

    Article  PubMed  CAS  Google Scholar 

  62. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3:169–78.

    Article  PubMed  CAS  Google Scholar 

  63. Nesto R. C-reactive protein, its role in inflammation, type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones. Diabet Med. 2004;21:810–7.

    Article  PubMed  CAS  Google Scholar 

  64. Doi Y, Kiyohara Y, Kubo M, Ninomiya T, Wakugawa Y, Yonemoto K, et al. Elevated c-reactive protein is a predictor of the development of diabetes in a general Japanese population: the Hisayama Study. Diabetes Care. 2005;28:2497–500.

    Article  PubMed  CAS  Google Scholar 

  65. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk In Communities Study): a cohort study. Lancet. 1999;353:1649–52.

    Article  PubMed  CAS  Google Scholar 

  66. Lee CC, Adler AI, Sandhu MS, Sharp SJ, Forouhi NG, Erqou S, et al. Association of c-reactive protein with type 2 diabetes: prospective analysis and meta-analysis. Diabetologia. 2009;52:1040–7.

    Article  PubMed  CAS  Google Scholar 

  67. Schram MT, Euser SM, de Craen AJ, Witteman JC, Frolich M, Hofman A, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc. 2007;55:708–16.

    Article  PubMed  Google Scholar 

  68. Alley DE, Crimmins EM, Karlamangla A, Hu P, Seeman TE. Inflammation and rate of cognitive change in high-functioning older adults. J Gerontol A Biol Sci Med Sci. 2008;63:50–5.

    Article  PubMed Central  PubMed  Google Scholar 

  69. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A. Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int Rev Neurobiol. 2007;82:235–46.

    Article  PubMed  CAS  Google Scholar 

  70. Fuster-Matanzo A, Llorens-Martín M, Hernández F, Avila J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediators Inflamm. 2013;2013:260925.

    Article  PubMed Central  PubMed  Google Scholar 

  71. Xia MQ, Hyman BT. Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. J Neurovirol. 1999;5:32–41.

    Article  PubMed  CAS  Google Scholar 

  72. Marioni RE, Strachan MW, Reynolds RM, Lowe GD, Mitchell RJ, Fowkes FG, et al. Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes. 2010;59:710–3.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65:545–51.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Toshiharu Ninomiya declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Toshiharu Ninomiya.

Additional information

This article is part of the Topical Collection on Diabetes and Other Diseases-Emerging Associations

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ninomiya, T. Diabetes Mellitus and Dementia. Curr Diab Rep 14, 487 (2014). https://doi.org/10.1007/s11892-014-0487-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-014-0487-z

Keywords

Navigation