Diabetes Mellitus and Dementia

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.

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References

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

  1. 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. 2.

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

  3. 3.

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

  4. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  5. 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.

    PubMed  Article  Google Scholar 

  6. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  7. 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.

    PubMed  Article  CAS  Google Scholar 

  8. 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.

    PubMed  Article  CAS  Google Scholar 

  9. 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.

    PubMed  Article  CAS  Google Scholar 

  10. 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.

    PubMed  Article  CAS  Google Scholar 

  11. 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.

    PubMed  Article  Google Scholar 

  12. 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.

    PubMed  Article  CAS  Google Scholar 

  13. 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.

    PubMed  Article  Google Scholar 

  14. 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.

    PubMed  Article  Google Scholar 

  15. 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.

    PubMed  Article  Google Scholar 

  16. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  17. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  18. 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.

    PubMed  Article  CAS  Google Scholar 

  19. 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.

    PubMed  Article  CAS  Google Scholar 

  20. 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.

    PubMed  Article  CAS  Google Scholar 

  21. 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. 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.

    PubMed  Article  CAS  Google Scholar 

  23. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  24. 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.

    PubMed  Article  Google Scholar 

  25. 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.

    PubMed  Article  Google Scholar 

  26. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  27. 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.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

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

    PubMed  Article  CAS  Google Scholar 

  29. 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.

    PubMed  Article  CAS  Google Scholar 

  30. 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.

    PubMed  Article  CAS  Google Scholar 

  31. 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.

    PubMed  Article  Google Scholar 

  32. 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.

    PubMed  Article  CAS  Google Scholar 

  33. 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. 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.

    PubMed  Article  CAS  Google Scholar 

  35. 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.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

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

    PubMed  Article  Google Scholar 

  37. 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.

    PubMed  Article  CAS  Google Scholar 

  38. 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.

    PubMed  Article  CAS  Google Scholar 

  39. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  40. 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. 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.

    PubMed  Article  CAS  Google Scholar 

  42. 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. 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.

    PubMed  Article  Google Scholar 

  44. 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.

    PubMed  Article  CAS  Google Scholar 

  45. 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.

    PubMed  Article  Google Scholar 

  46. 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.

    PubMed  Article  Google Scholar 

  47. 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.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

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

    PubMed  Article  CAS  Google Scholar 

  49. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  50. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  51. 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.

    PubMed  Article  Google Scholar 

  52. 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.

    PubMed  Article  CAS  Google Scholar 

  53. 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.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

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

    PubMed  Article  CAS  Google Scholar 

  55. 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.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

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

    PubMed  Article  CAS  Google Scholar 

  57. 57.

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

    PubMed  Article  CAS  Google Scholar 

  58. 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.

    PubMed  Article  CAS  Google Scholar 

  59. 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. 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.

    PubMed  Article  CAS  Google Scholar 

  61. 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.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

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

    PubMed  Article  CAS  Google Scholar 

  63. 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.

    PubMed  Article  CAS  Google Scholar 

  64. 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.

    PubMed  Article  CAS  Google Scholar 

  65. 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.

    PubMed  Article  CAS  Google Scholar 

  66. 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.

    PubMed  Article  CAS  Google Scholar 

  67. 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.

    PubMed  Article  Google Scholar 

  68. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  69. 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.

    PubMed  Article  CAS  Google Scholar 

  70. 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.

    PubMed Central  PubMed  Article  Google Scholar 

  71. 71.

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

    PubMed  Article  CAS  Google Scholar 

  72. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  73. 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.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

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Toshiharu Ninomiya declares that he has no conflict of interest.

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Correspondence to Toshiharu Ninomiya.

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

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

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Keywords

  • Diabetes mellitus
  • Dementia
  • Alzheimer’s disease
  • Vascular dementia
  • Epidemiology
  • Prospective study