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Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems

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Abstract

Type 2 diabetes mellitus is associated with an increased risk to develop Alzheimer disease, however, the underlying mechanisms for this association are still unclear. In this review we will provide a critical overview of the major findings coming from clinical studies and animal models.

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References

  1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63:168

    Article  PubMed  Google Scholar 

  2. Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:77sr1

    PubMed  PubMed Central  Google Scholar 

  3. Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 1812:1630–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  5. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WPT, Loria CM, Smith SC (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Association for the Study of Obesity. Circulation 120:1640–1645

    Article  CAS  PubMed  Google Scholar 

  6. Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB (2011) Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? Br J Clin Pharmacol 71:365–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Donaghue KC, Chiarelli F, Trotta D, Allgrove J, Dahl-Jorgensen K (2009) Microvascular and macrovascular complications associated with diabetes in children and adolescents. Pediatr Diabetes 10:195–203

    Article  PubMed  Google Scholar 

  8. Kodl CT, Seaquist ER (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29:494–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brands AMA, Biessels GJ, de Haan EHF, Kappelle LJ, Kessels RPC (2005) The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28:726–735

    Article  PubMed  Google Scholar 

  10. Geijselaers SLC, Sep SJS, Claessens D, Schram MT, van Boxtel MPJ, Henry RMA, Verhey FRJ, Kroon AA, Dagnelie PC, Schalkwijk CG, van der Kallen CJH, Biessels GJ, Stehouwer CDA (2017) The role of hyperglycemia, insulin resistance, and blood pressure in diabetes-associated differences in cognitive performance—the Maastricht Study. Diabetes Care 40:1537–1547

    Article  CAS  PubMed  Google Scholar 

  11. Lindeman RD, Romero LJ, LaRue A, Yau CL, Schade DS, Koehler KM, Baumgartner RN, Garry PJ, New Mexico Elder Health Survey (2001) A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico Elder Health Survey. Diabetes Care 24:1567–1572

    Article  CAS  PubMed  Google Scholar 

  12. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53:1937–1942

    Article  CAS  PubMed  Google Scholar 

  13. Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K (1995) Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology 45:1161–1168

    Article  CAS  PubMed  Google Scholar 

  14. Schnaider Beeri M, Goldbourt U, Silverman JM, Noy S, Schmeidler J, Ravona-Springer R, Sverdlick A, Davidson M (2004) Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology 63:1902–1907

    Article  CAS  PubMed  Google Scholar 

  15. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, Palumbo PJ (1997) Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 145:301–308

    Article  CAS  PubMed  Google Scholar 

  16. Peila R, Rodriguez BL, Launer LJ, Honolulu-Asia Aging Study (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51:1256–1262

    Article  CAS  PubMed  Google Scholar 

  17. Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, Haneuse S, Craft S, Montine TJ, Kahn SE, McCormick W, McCurry SM, Bowen JD, Larson EB (2013) Glucose levels and risk of dementia. N Engl J Med 369:540–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yaffe K, Blackwell T, Whitmer R, Krueger K, Barrett Connor E (2006) Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging 10:293–295

    CAS  PubMed  Google Scholar 

  19. Scott RD, Kritz-Silverstein D, Barrett-Connor E, Wiederholt WC (1998) The association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort. J Am Geriatr Soc 46:1217–1222

    Article  CAS  PubMed  Google Scholar 

  20. Euser SM, Sattar N, Witteman JCM, Bollen ELEM, Sijbrands EJG, Hofman A, Perry IJ, Breteler MMB, Westendorp RGJ, PROSPER and Rotterdam Study for P and the R (2010) A prospective analysis of elevated fasting glucose levels and cognitive function in older people: results from PROSPER and the Rotterdam Study. Diabetes 59:1601–1607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, Sullivan M, Horowitz KR, Ding J, Marcovina S, Lovato LC, Lovato J, Margolis KL, Connor PO, Lipkin EW, Hirsh J (2012) Effects of randomization to intensive glucose lowering on brain structure and function in type 2 diabetes ACCORD Memory. Diabetes Study 10:969–977

    Google Scholar 

  22. Li W, Risacher SL, Huang E, Saykin AJ, Alzheimer’s Disease Neuroimaging Initiative F the ADN (2016) Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort. Neurology 87:595–600

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68:51–57

    Article  PubMed  Google Scholar 

  24. Roberts RO, Knopman DS, Cha RH, Mielke MM, Pankratz VS, Boeve BF, Kantarci K, Geda YE, Jack CR, Petersen RC, Lowe VJ (2014) Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med 55:759–764

    Article  CAS  PubMed  Google Scholar 

  25. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42:85–94

    Article  CAS  PubMed  Google Scholar 

  26. Langbaum JBS, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM, Alzheimer’s Disease Neuroimaging Initiative (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuroimage 45:1107–1116

    Article  PubMed  Google Scholar 

  27. Biessels GJ, Reijmer YD (2014) Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63:2244–2252

    Article  PubMed  Google Scholar 

  28. Vermeer SE, Den Heijer T, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MMB, Rotterdam Scan Study (2003) Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 34:392–396

    Article  PubMed  Google Scholar 

  29. Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC (2012) Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 12:148–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hou Q, Zuo Z, Michel P, Zhang Y, Eskandari A, Man F, Gao Q, Johnston KC, Wintermark M (2013) Influence of chronic hyperglycemia on cerebral microvascular remodeling: an in vivo study using perfusion computed tomography in acute ischemic stroke patients. Stroke 44:3557–3560

    Article  PubMed  Google Scholar 

  31. de Bresser J, Tiehuis AM, van den Berg E, Reijmer YD, Jongen C, Kappelle LJ, Mali WP, Viergever MA, Biessels GJ, Utrecht Diabetic Encephalopathy Study Group (2010) Progression of cerebral atrophy and white matter hyperintensities in patients with type 2 diabetes. Diabetes Care 33:1309–1314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MMB (2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46:1604–1610

    Article  Google Scholar 

  33. Schmidt R, Launer LJ, Nilsson L-G, Pajak A, Sans S, Berger K, Breteler MM, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Hofman A, CASCADE Consortium (2004) Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 53:687–692

    Article  CAS  PubMed  Google Scholar 

  34. Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, Tsui W, Richardson S, Javier E, Convit A (2007) Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50:711–719

    Article  CAS  PubMed  Google Scholar 

  35. Reijmer YD, Brundel M, de Bresser J, Kappelle LJ, Leemans A, Biessels GJ, Utrecht Vascular Cognitive Impairment Study Group on behalf of the UVCIS (2013) Microstructural white matter abnormalities and cognitive functioning in type 2 diabetes: a diffusion tensor imaging study. Diabetes Care 36:137–144

    Article  PubMed  Google Scholar 

  36. Musen G, Jacobson AM, Bolo NR, Simonson DC, Shenton ME, McCartney RL, Flores VL, Hoogenboom WS (2012) Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes 61:2375–2379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McEwen BS, Reagan LP (2004) Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 490:13–24

    Article  CAS  PubMed  Google Scholar 

  38. Banks WA, Owen JB, Erickson MA (2012) Insulin in the brain: there and back again. Pharmacol Ther 136:82–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Banks WA, Jaspan JB, Kastin AJ (1997) Selective, physiological transport of insulin across the blood–brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 18:1257–1262

    Article  CAS  PubMed  Google Scholar 

  40. Wallum BJ, Taborsky GJ, Porte D, Figlewicz DP, Jacobson L, Beard JC, Ward WK, Dorsa D (1987) Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 64:190–194

    Article  CAS  PubMed  Google Scholar 

  41. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong C-X (2011) Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol 225:54–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stanley M, Macauley SL, Holtzman DM (2016) Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J Exp Med 213:1375–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis 7:63–80

    Article  CAS  PubMed  Google Scholar 

  44. Ho L, Yemul S, Knable L, Katsel P, Zhao R, Haroutunian V, Pasinetti GM (2012) Insulin receptor expression and activity in the brains of nondiabetic sporadic Alzheimer’s disease cases. Int J Alzheimers Dis 2012, 1–12

  45. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 31:224–243

    Article  CAS  PubMed  Google Scholar 

  46. Baranowska-Bik A, Bik W (2017) Insulin and brain aging. Prz Menopauzalny 16:44–46

    PubMed  PubMed Central  Google Scholar 

  47. Frölich FL, Blum-Degen D, Bernstein H-G, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S, Zöchling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 105:423

    Article  PubMed  Google Scholar 

  48. Avgerinos KI, Kalaitzidis G, Malli A, Kalaitzoglou D, Myserlis PG, Lioutas V-A (2018) Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: a systematic review. J Neurol 265:1497–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Reger MA, Craft S (2006) Intranasal insulin administration: a method for dissociating central and peripheral effects of insulin. Drugs Today 42:729

    Article  CAS  Google Scholar 

  50. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 100, 4162–4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Behl M, Zhang Y, Zheng W (2009) Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood–CSF barrier: consequences of lead exposure. Cerebrospinal Fluid Res 6:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin L-W, Kovacina KS, Craft S (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 162:313–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Avila J, León-Espinosa G, García E, García-Escudero V, Hernández F, DeFelipe J (2012) Tau phosphorylation by GSK3 in different conditions. Int J Alzheimers Dis 2012:1–7

    Article  CAS  Google Scholar 

  54. Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  CAS  PubMed  Google Scholar 

  55. Negre-Salvayre A, Salvayre R, Augé N, Pamplona R, Portero-Otín M (2009) Hyperglycemia and glycation in diabetic complications. Antioxid Redox Signal 11:3071–3109

    Article  CAS  PubMed  Google Scholar 

  56. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama Study. Neurology 75:764–770

    Article  CAS  PubMed  Google Scholar 

  57. Thambisetty M, Metter EJ, Yang A, Dolan H, Marano C, Zonderman AB, Troncoso JC, Zhou Y, Wong DF, Ferrucci L, Egan J, Resnick SM, O’Brien RJ (2013) Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol 70:1167

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, Sulkava R, Kivipelto M (2010) Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75:1195–1202

    Article  CAS  PubMed  Google Scholar 

  59. Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, Davis GJ, Keller JN, Jicha GA, Davis D, Wang-Xia W, Hartman A, Katz DG, Markesbery WR (2009) Human cerebral neuropathology of Type 2 diabetes mellitus. Biochim Biophys Acta 1792:454–469

    Article  CAS  PubMed  Google Scholar 

  60. Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16:660–671

    Article  CAS  PubMed  Google Scholar 

  61. Gault VA, Kerr BD, Harriott P, Flatt PR (2011) Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity. Clin Sci 121:107–117

    Article  CAS  Google Scholar 

  62. Graham ML, Janecek JL, Kittredge JA, Hering BJ, Schuurman H-J (2011) The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp Med 61:356–360

    CAS  PubMed  PubMed Central  Google Scholar 

  63. King AJF (2012) The use of animal models in diabetes research. Br J Pharmacol 166:877–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Heydemann A, Ahlke (2016) An overview of murine high fat diet as a model for Type 2 diabetes mellitus. J Diabetes Res 2016:1–14

    Article  CAS  Google Scholar 

  65. Hariri N, Thibault L (2010) High-fat diet-induced obesity in animal models. Nutr Res Rev 23:270–299

    Article  CAS  PubMed  Google Scholar 

  66. Burcelin R, Crivelli V, Dacosta A, Roy-Tirelli A, Thorens B (2002) Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet. Am J Physiol Endocrinol Metab 282:E834–E842

    Article  CAS  PubMed  Google Scholar 

  67. Kaneto H, Katakami N, Matsuhisa M, Matsuoka T (2010) Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm 2010: 453892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Muriach M, Flores-Bellver M, Romero FJ, Barcia JM (2014) Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014:102158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Balbaa M, Abdulmalek SA, Khalil S (2017) Oxidative stress and expression of insulin signaling proteins in the brain of diabetic rats: role of Nigella sativa oil and antidiabetic drugs. PLoS ONE 12:e0172429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN, Uranga RM, Bruce-Keller AJ, Keller JN (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114:1581–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Studzinski CM, Li F, Bruce-Keller AJ, Fernandez-Kim SO, Zhang L, Weidner AM, Markesbery WR, Murphy MP, Keller JN (2009) Effects of short-term Western diet on cerebral oxidative stress and diabetes related factors in APP × PS1 knock-in mice. J Neurochem 108:860–866

    Article  CAS  PubMed  Google Scholar 

  72. Tsai M-J, Lin M-W, Huang Y-B, Kuo Y-M, Tsai Y-H (2016) The influence of acute hyperglycemia in an animal model of lacunar stroke that is induced by artificial particle embolization. Int J Med Sci 13:347–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM (2015) Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest 125:2463–2467

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J 18:902–904

    Article  CAS  PubMed  Google Scholar 

  75. Arnold SE, Lucki I, Brookshire BR, Carlson GC, Browne CA, Kazi H, Bang S, Choi B-R, Chen Y, McMullen MF, Kim SF (2014) High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol Dis 67:79–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vandal M, White PJ, Tremblay C, St-Amour I, Chevrier G, Emond V, Lefrancois D, Virgili J, Planel E, Giguere Y, Marette A, Calon F (2014) Insulin reverses the high-fat diet-induced increase in brain A and improves memory in an animal model of Alzheimer disease. Diabetes 63:4291–4301

    Article  CAS  PubMed  Google Scholar 

  77. Salas IH, Weerasekera A, Ahmed T, Callaerts-Vegh Z, Himmelreich U, D’Hooge R, Balschun D, Saido TC, De Strooper B, Dotti CG (2018) High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease. Neurobiol Dis 113:82–96

    Article  CAS  Google Scholar 

  78. Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53(2):474–481

    Article  Google Scholar 

  79. Pedersen WA, Flynn ER (2004) Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 17:500–506

    Article  CAS  PubMed  Google Scholar 

  80. Vandal M, White P, Chevrier G, Tremblay C, St.-Amour I, Planel E, Marette A, Calon F (2015) Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer’s disease. FASEB J 29:4273–4284

    Article  CAS  PubMed  Google Scholar 

  81. Velazquez R, Tran A, Ishimwe E, Denner L, Dave N, Oddo S, Dineley KT (2017) Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer’s disease. Neurobiol Aging 58:1–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Petrov D, Pedrós I, Artiach G, Sureda FX, Barroso E, Pallàs M, Casadesús G, Beas-Zarate C, Carro E, Ferrer I, Vazquez-Carrera M, Folch J, Camins A (2015) High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents. Biochim Biophys Acta 1852:1687–1699

    Article  CAS  PubMed  Google Scholar 

  83. Knight EM, Martins IVA, Gümüsgöz S, Allan SM, Lawrence CB (2014) High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 35:1821–1832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Busquets O, Ettcheto M, Pallàs M, Beas-Zarate C, Verdaguer E, Auladell C, Folch J, Camins A (2016) Long-term exposition to a high fat diet favors the appearance of β-amyloid depositions in the brain of C57BL/6J mice. A potential model of sporadic Alzheimer’s disease. Mech. Ageing Dev 162:38–45

    Google Scholar 

  85. Moreira PI, Santos MS, Seiça R, Oliveira CR (2007) Brain mitochondrial dysfunction as a link between Alzheimer’s disease and diabetes. J Neurol Sci 257:206–214

    Article  CAS  PubMed  Google Scholar 

  86. Moreira PI, Santos MS, Moreno AM, Seiça R, Oliveira CR (2003) Increased vulnerability of brain mitochondria in diabetic (Goto–Kakizaki) rats with aging and amyloid-beta exposure. Diabetes 52:1449–1456

    Article  CAS  PubMed  Google Scholar 

  87. Jørgensen T, Grunnet N, Quistorff B (2015) One-year high fat diet affects muscle—but not brain mitochondria. J Cereb Blood Flow Metab 35:943–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Carvalho C, Cardoso S, Correia SC, Santos RX, Santos MS, Baldeiras I, Oliveira CR, Moreira PI (2012) Metabolic Alterations induced by sucrose intake and Alzheimer’s disease promote similar brain mitochondrial abnormalities. Diabetes 61:1234–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McManus MJ, Murphy MP, Franklin JL (2011) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci 31:15703–15715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Haslam D, Sattar N, Lean M (2006) ABC of obesity. Obesity—time to wake up. BMJ 333:640–642

    Article  PubMed  PubMed Central  Google Scholar 

  91. Beydoun MA, Beydoun HA, Wang Y (2008) Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obes Rev 9:204–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  PubMed  Google Scholar 

  93. Guillemot-Legris O, Muccioli GG (2017) Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci 40:237–253

    Article  CAS  PubMed  Google Scholar 

  94. Buckman L, Hasty A, Flaherty D, Buckman C, Thompson M, Matlock B, Weller K, Ellacott K (2014) Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun 35:33–42

    Article  CAS  PubMed  Google Scholar 

  95. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJA, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199

    Article  CAS  PubMed  Google Scholar 

  96. Moreno-Gonzalez I, Edwards IIIG, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C (2017) Molecular interaction between type 2 diabetes and Alzheimer’s disease through cross-seeding of protein misfolding. Mol Psychiatry 22:1327–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jackson K, Barisone GA, Diaz E, Jin L, DeCarli C, Despa F (2013) Amylin deposition in the brain: a second amyloid in Alzheimer disease? Ann Neurol 74:517–526

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Isabel H. Salas.

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Special issue: In honor of Prof Anthony J. Turner.

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Salas, I.H., De Strooper, B. Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems. Neurochem Res 44, 1271–1278 (2019). https://doi.org/10.1007/s11064-018-2690-9

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