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Does Diabetes Protect or Provoke Alzheimer's Disease? Insights Into the Pathobiology and Future Treatment of Alzheimer's Disease

Published online by Cambridge University Press:  07 November 2014

Hillel Grossman
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Abstract

Diabetes mellitus has long been considered a risk factor for the development of vascular dementia. Epidemiologic evidence has suggested that diabetes mellitus significantly increases risk for the development of Alzheimer's disease, independent of vascular risk factors. As insulin's role as a neuromodulator in the brain has been described, its significance for AD has also emerged. Insulin dysregulation may contribute to AD pathology through several mechanisms including decreased cortical glucose utilization particularly in the hippocampus and entorhinal cortex; increased oxidative stress through the formation of advanced glycation end-products; increased Tau phosphorylation and neurofibrillary tangle formation; increased β-amyloid aggregation through inhibition of insulin-degrading enzyme. Future treatment of AD might involve pharmacologic and dietary manipulations of insulin and glucose regulation.

Type
Review
Information
CNS Spectrums , Volume 8 , Issue 11: Alzheimer's Disease in the 21st Century , November 2003 , pp. 815 - 822
Copyright
Copyright © Cambridge University Press 2003

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References

REFERENCES

1.Brun, A, Englund, E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol. 1986;19:253–262.CrossRefGoogle Scholar
2.Chui, H. Vascular dementia, a new beginning: shifting focus from clinical phenotype to ischemic brain injury. Neurol Clin. 2000;18:951–78.CrossRefGoogle ScholarPubMed
3.Kalaria, R. Similarities between Alzheimer's disease and vascular dementia. J Neurol Sci. 2002;203–204:29–34.CrossRefGoogle ScholarPubMed
4.Launer, LJ. Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Aging Res Rev. 2002;1:61–77.CrossRefGoogle ScholarPubMed
5.Schulingkamp, RJ, Pagano, TC, Hung, D, Raffa, RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24:855–872.CrossRefGoogle ScholarPubMed
6.Wolf-Klein, GP, Siverstone, FA, Brod, MS, et al. Are Alzheimer patients healthier? J Am Geriatr Soc. 1988;36:219–224.CrossRefGoogle ScholarPubMed
7.Mortel, KF, Wood, S, Pavol, MA, Meyer, JS, Rexer, JL. Analysis of familial and individual risk factors among patients with ischemic vascular dementia and Alzheimer's disease. Angiology. 1993;44:599–605.CrossRefGoogle ScholarPubMed
8.Landin, K, Blennow, K, Wallin, A, Gottfries, CG. Low blood pressure and blood glucose levels in Alzheimer's disease. Evidence for a hypometabolic disorder? J Intern Med. 1993;233:357–363.CrossRefGoogle ScholarPubMed
9.Nielson, KA, Nolan, JH, Berchtold, NC, Sandman, CA, Mulnard, RA, Cotman, CW. Apolipoprotein-E genotyping of diabetic dementia patients: is diabetes rare in Alzheimer's disease? J Am Geriatr Soc. 1996;44:897–904.CrossRefGoogle ScholarPubMed
10.Tariot, PN, Ogden, MA, Cox, C, Williams, TF. Diabetes and dementia in long-term care. J Am Geriatr Soc. 1999;47:423–429.CrossRefGoogle ScholarPubMed
11.Bennett, DA. Diabetes and change in cognitive function. Arch Intern Med. 2000;160:141–143.CrossRefGoogle ScholarPubMed
12.Yoshitake, T, Kiyohara, Y, Kato, I, et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995;45:1161–1168.CrossRefGoogle Scholar
13.Leibson, CL, Rocca, WA, Hanson, VA, et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann N Y Acad Sci. 1997;826:422–427.CrossRefGoogle ScholarPubMed
14.Ott, A, Stolk, RP, Hofman, A, van Harskamp, F, Grobbee, DE, Breteler, MM. Association of diabetes mellitus and dementia: The Rotterdam Study. Diabetologia. 1996;39:1392–1397.CrossRefGoogle ScholarPubMed
15.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;53:1937–1942.CrossRefGoogle ScholarPubMed
16.Curb, JD, Rodriguez, BL, Abbott, RD, et al. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology. 1999;52:971–975.CrossRefGoogle ScholarPubMed
17.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;51:1256–1262.CrossRefGoogle ScholarPubMed
18.Kuusisto, J, Koivisto, K, Mykkanen, L, et al. Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein e4 phenotype: cross sectional population based study. BMJ. 1997;315:1045–1049.CrossRefGoogle ScholarPubMed
19.Craft, S, Dagogo-Jack, SE, Wiethop, BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neuroscience. 1993;107:926–940.CrossRefGoogle ScholarPubMed
20.Craft, S, Newcomer, J, Kanne, S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging. 1996;17:123–130.CrossRefGoogle ScholarPubMed
21.Craft, S, Asthana, S, Schellenberg, G, et al. Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology. 1999;70:146–152.CrossRefGoogle ScholarPubMed
22.Bucht, G, Adolfsson, R, Lithner, F, Winblad, B. Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. Acta Med Scand. 1983;213:387–392.CrossRefGoogle ScholarPubMed
23.Fujisawa, Y, Sasaki, K, Akiyama, K. Increased insulin levels after OGTT load in peripheral blood and cerebrospinal fluid of patients with dementia of Alzheimer type. Biol Psychiatry. 1991;30:1219–1228.CrossRefGoogle ScholarPubMed
24.Heitner, J, Dickson, D. Diabetics do not have increased Alzheimertype pathology compared with age-matched control subjects. Neurology. 1997;49:1306–1311.CrossRefGoogle Scholar
25.Silverman, JM, Smith, CM, Marin, DB, et al. Has familial aggregation in Alzheimer's disease been overestimated? Int J Geriatr Psychiatry. 2000;15:631–637.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
26.Silverman, JM, Smith, CJ, Marin, DB, Mohs, RC, Propper, CB. Familial patterns of risk in very late-onset Alzheimer disease. Arch Gen Psychiatry. 2003;60:190–197.CrossRefGoogle ScholarPubMed
27.Bruning, JC, Gautam, D, Burks, DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–2125.CrossRefGoogle ScholarPubMed
28.Hoyer, S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease. A mini-review. J Neural Transm. 2002;109:991–1002.CrossRefGoogle ScholarPubMed
29.Gasparini, L, Netzer, WJ, Greengard, P, Xu, H. Does insulin dysfunction play a role in Alzheimer's disease? Trends Pharmacol Sci. 2002;23:288–293.CrossRefGoogle ScholarPubMed
30.Craft, S, Peskind, E, Schwartz, MW, Schellenberg, GD, Raskind, M, Porte, D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease. Neurology. 1998;50:164–168CrossRefGoogle ScholarPubMed
31.Watson, GS, Peskind, ER, Asthana, S, et al. Insulin increases CSF Abeta-42 levels in normal older adults. Neurology. 2003;60:1899–1903.CrossRefGoogle Scholar
32.de Leon, MJ, Convit, A, Wolf, OT, et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001;98:10966–10971.CrossRefGoogle Scholar
33.De Santi, S, de Leon, MJ, Rusinek, H, et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging. 2001;22:529–539CrossRefGoogle ScholarPubMed
34.Aisen, PS, Berg, JD, Craft, S, et al. Steroid-induced elevation of glucose in Alzheimer's disease: relationship to gender, apolipoprotein E genotype and cognition. Psychoneuroendocrinology. 2003;28:113–120.CrossRefGoogle ScholarPubMed
35.Kyriaki, G. Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol. 2003;23:1–25.Google Scholar
36.Hoyer, S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm. 1998;105:415–422.CrossRefGoogle ScholarPubMed
37.Frolich, L, Blum-Degen, D, Bernstein, HG, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm. 1998;105:423–438.CrossRefGoogle ScholarPubMed
38.Frolich, L, Blum-Degen, D, Riederer, P, Hoyer, S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci. 1999;893:290–293.CrossRefGoogle ScholarPubMed
39.Schubert, M, Brazil, DP, Burks, DJ, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003;23:7084–7092.CrossRefGoogle ScholarPubMed
40.Liolitsa, D, Powell, J, Lovestone, S. Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2002;73:261–266.CrossRefGoogle Scholar
41.Gasic-Milenkovic, J, Loske, C, Munch, G. Advanced glycation end-products cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimer Dis. 2003;5:25–30.CrossRefGoogle ScholarPubMed
42.Uribarri, J, Peppa, M, Cai, W, et al. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J Am Soc Nephrol. 2003;14:728–731.CrossRefGoogle ScholarPubMed
43.Munch, G, Thome, J, Foley, P, Schinzel, R, Riederer, P. Advanced glycation end-products in ageing and Alzheimer's disease. Brain Res Rev. 1997;23:134–143.CrossRefGoogle ScholarPubMed
44.Vitek, MP, Bhattacharya, K, Glendening, JM, et al. Advanced glycation end-products contribute to amyloidosis in Alzheimer's disease. Proc Nat Acad Sci. 1994;91:766–4770CrossRefGoogle Scholar
45.Dickson, DW, Sinicropi, S, Yen, SH, et al. Glycation and microglial reaction in lesions of Alzheimer's disease. Neurobiol Aging. 1996;17:733–743CrossRefGoogle ScholarPubMed
46.Munch, G, Schinzel, R, Loske, C, et al. Alzheimer's disease—synergistic effects of glucose deficit, oxidative stress and advanced glycation end-products. J Neural Transm. 1998;20:246–266.Google Scholar
47.Tanaka, Y, Uchino, H, Shimizu, T, et al. Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats. Eur J Pharm. 1999;376:17–22CrossRefGoogle ScholarPubMed
48.Taubes, G. Insulin insults may spur Alzheimer's disease. Science. 2003;301:40–41.CrossRefGoogle ScholarPubMed
49.Galasko, D. Insulin and Alzheimer's disease: an amyloid connection. Neurology. 2003;60:1886–1887.CrossRefGoogle ScholarPubMed
50.Graeber, MB, Mehraein, P. Reanalysis of the first case of Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 1999;249 (suppl 3):10–13.CrossRefGoogle ScholarPubMed
51.Selkoe, DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001;32:177–180.CrossRefGoogle ScholarPubMed
52.Selkoe, DJ. Alzheimer's disease: genes, proteins, and therapy. Psychol Rev. 2001;81:741–766.Google ScholarPubMed
53.Savage, MJ, Trusko, SP, Howland, DS, et al. Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci. 1998;18:1743–1752.CrossRefGoogle ScholarPubMed
54.Kurochkin, IV, Goto, S. Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345:33–37.CrossRefGoogle ScholarPubMed
55.Kurochkin, IV. Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS Lett. 1998;427:153–156.CrossRefGoogle ScholarPubMed
56.McDermott, JR, Gibson, AM. Degradation of Alzheimer's betaamyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. Neurochem Res. 1997;22:49–56CrossRefGoogle ScholarPubMed
57.Qiu, WQ, Walsh, DM, Ye, Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998;273:32730–32738CrossRefGoogle ScholarPubMed
58.Chesneau, V, Vekrellis, K, Rosner, MR, Selkoe, DJ. Purified recombinant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization. Biochem J. 2000;351:509–516.CrossRefGoogle Scholar
59.Vekrellis, K, Ye, Z, Qiu, WQ, et al. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000;20:1657–1665.CrossRefGoogle ScholarPubMed
60.Mukherjee, A, Song, E, Kihiko-Ehmann, M, et al. Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques. J Neurosci. 2000;20:8745–8749.CrossRefGoogle ScholarPubMed
61.Perez, A, Morelli, L, Cresto, JC, Castano, EM. Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem Res. 2000;25:247–255.CrossRefGoogle ScholarPubMed
62.Bernstein, HG, Ansorge, S, Riederer, P, Reiser, M, Frolich, L, Bogerts, B. Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques. Neurosci Lett. 1999;3:161–164.CrossRefGoogle Scholar
63.Sudoh, S, Frosch, MP, Wolf, BA. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and -insoluble pools in CHO-695 cells. Biochemistry. 2002;41:1091–1099.CrossRefGoogle ScholarPubMed
64.Edbauer, D, Willem, M, Lammich, S, Steiner, H, Haass, C. Insulindegrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). J Biol Chem. 2002;277(16):13389–13393.CrossRefGoogle Scholar
65.Cook, DG, Leverenz, JB, McMillan, PJ, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003;162:313–319.CrossRefGoogle ScholarPubMed
66.Farris, W, Mansourian, S, Chang, Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the betaamyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100:4162–4167.CrossRefGoogle ScholarPubMed
67.Hamel, FG, Bennett, RG, Duckworth, WC. Regulation of multicatalytic enzyme activity by insulin and the insulin-degrading enzyme. Endocrinology. 1998;139:4061–4066.CrossRefGoogle ScholarPubMed
68.Gasparini, L, Gouras, GK, Wang, R, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21:2561–2570.CrossRefGoogle ScholarPubMed
69.Myers, A, Holmans, P, Marshall, H, et al. Susceptibility locus for Alzheimer's disease on chromosome 10. Science. 2000;290:2304–2305.CrossRefGoogle ScholarPubMed
70.Ertekin-Taner, N, Graff-Radford, N, Younkin, LH, et al. Heritability of plasma amyloid β in typical late-onset Alzheimer's disease pedigrees. Genet Epidemiol. 2001;21:19–30.CrossRefGoogle ScholarPubMed
71.Bertram, L, Blacker, D, Mullin, K, et al. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science. 2000;290:2302–2303.CrossRefGoogle ScholarPubMed
72.Abraham, R, Myers, A, Wavrant-DeVrieze, F, et al. Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease. Hum Genet. 2001;109:646–652.CrossRefGoogle ScholarPubMed
73.Luchsinger, JA, Tang, MX, Stem, 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;154:635–641.CrossRefGoogle Scholar
74.Landreth, GE, Heneka, MT. Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheime's disease. Neurobiol Aging. 2001;22:937–944.CrossRefGoogle Scholar
75.Combs, CK, Johnson, DE, Karlo, JC, Cannady, SB, Landreth, GE. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci. 2000;20:558–567.CrossRefGoogle ScholarPubMed