Diabetes and Alzheimer disease (AD)—two age-related diseases—are both increasing in prevalence, and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood. Abnormal protein processing, abnormalities in insulin signaling, dysregulated glucose metabolism, oxidative stress, the formation of advanced glycation end products, and the activation of inflammatory pathways are features common to both diseases. Hypercholesterolemia is another factor that has received attention, owing to its potential association with diabetes and AD. This Review summarizes the mechanistic pathways that might link diabetes and AD. An understanding of this complex interaction is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases.
Alzheimer disease (AD) and diabetes are both associated with enormous and increasing socioeconomic effects
Diabetes affects the processing of amyloid-β and tau, and might increase the rate of formation of senile plaques and neurofibrillary tangles, the main neuropathological hallmarks of AD
Hyperinsulinemia is associated with amyloid-β accumulation and regulates tau phosphorylation
Oxidative stress activates inflammatory pathways and, hence, might exacerbate AD neuropathology
Mitochondrial dysfunction is associated with both diabetes and AD, and leads to intracellular calcium dysregulation and abnormal processing of the amyloid precursor protein
Induction of diabetes exacerbates AD neuropathology in mouse models of this neurodegenerative disease
Brands, A. M., Biessels, G. J., de Haan, E. H., Kappelle, L. J. & Kessels, R. P. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28, 726–735 (2005).
Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C. & Scheltens, P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5, 64–74 (2006).
Janson, J. et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53, 474–481 (2004).
Li, L. & Holscher, C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res. Rev. 56, 384–402 (2007).
Awad, N., Gagnon, M. & Messier, C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J. Clin. Exp. Neuropsychol. 26, 1044–1080 (2004).
Strachan, M. W., Deary, I. J., Ewing, F. M. & Frier, B. M. Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 20, 438–445 (1997).
Gilman, S. Alzheimer's disease. Perspect. Biol. Med. 40, 230–245 (1997).
Gotz, J., Schild, A., Hoerndli, F. & Pennanen, L. Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models. Int. J. Dev. Neurosci. 22, 453–465 (2004).
Rocchi, A., Pellegrini, S., Siciliano, G. & Murri, L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res. Bull. 61, 1–24 (2003).
Haan, M. N. Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease. Nat. Clin. Pract. Neurol. 2, 159–166 (2006).
Reddy, V. P., Zhu, X., Perry, G. & Smith, M. A. Oxidative stress in diabetes and Alzheimer's disease. J. Alzheimers Dis. 16, 763–774 (2009).
Hoyer, S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. 105, 415–422 (1998).
Nelson, T. J. & Alkon, D. L. Insulin and cholesterol pathways in neuronal function, memory and neurodegeneration. Biochem. Soc. Trans. 33, 1033–1036 (2005).
Zhao, W. Q. & Townsend, M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim. Biophys. Acta 1792, 482–496 (2009).
Martins, I. J. et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. Mol. Psychiatry 11, 721–736 (2006).
Moreira, P. I., Santos, M. S., Seica, R. & Oliveira, C. R. Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J. Neurol. Sci. 257, 206–214 (2007).
Nielson, K. A. et al. Apolipoprotein-E genotyping of diabetic dementia patients: is diabetes rare in Alzheimer's disease? J. Am. Geriatr. Soc. 44, 897–904 (1996).
Akomolafe, A. et al. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch. Neurol. 63, 1551–1555 (2006).
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. 14, 77–83 (2002).
Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Vetrivel, K. S. & Thinakaran, G. Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments. Neurology 66, S69–S73 (2006).
Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).
Small, D. H., Mok, S. S. & Bornstein, J. C. Alzheimer's disease and Aβ toxicity: from top to bottom. Nat. Rev. Neurosci. 2, 595–598 (2001).
Naslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 283, 1571–1577 (2000).
Hsia, A. Y. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228–3233 (1999).
Catalano, S. M. et al. The role of amyloid-β derived diffusible ligands (ADDLs) in Alzheimer's disease. Curr. Top. Med. Chem. 6, 597–608 (2006).
Johnson, G. V. & Stoothoff, W. H. Tau phosphorylation in neuronal cell function and dysfunction. J. Cell Sci. 117, 5721–5729 (2004).
Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005).
Rohn, T. T. et al. Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain. Neurobiol. Dis. 11, 341–354 (2002).
Chung, C. W. et al. Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol. Dis. 8, 162–172 (2001).
Gamblin, T. C., Berry, R. W. & Binder, L. I. Tau polymerization: role of the amino terminus. Biochemistry 42, 2252–2257 (2003).
Hrnkova, M., Zilka, N., Minichova, Z., Koson, P. & Novak, M. Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res. 1130, 206–213 (2007).
Chun, W. & Johnson, G. V. The role of tau phosphorylation and cleavage in neuronal cell death. Front. Biosci. 12, 733–756 (2007).
Kim, B., Backus, C., Oh, S., Hayes, J. M. & Feldman, E. L. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150, 5294–5301 (2009).
Li, Z. G., Zhang, W. & Sima, A. A. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56, 1817–1824 (2007).
Clodfelder-Miller, B. J., Zmijewska, A. A., Johnson, G. V. & Jope, R. S. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes 55, 3320–3325 (2006).
Planel, E. et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 27, 13635–13648 (2007).
Jolivalt, C. G. et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J. Neurosci. Res. 86, 3265–3274 (2008).
Liu, Y., Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C.-X. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer disease. J. Neurochem. 111, 242–249 (2009).
Dias, W. B. & Hart, G. W. O-GlcNAc modification in diabetes and Alzheimer's disease. Mol. Biosyst. 3, 766–772 (2007).
Biessels, G. J. et al. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res. 800, 125–135 (1998).
Stolk, R. P. et al. Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care 20, 792–795 (1997).
Zhao, W. Q. & Alkon, D. L. Role of insulin and insulin receptor in learning and memory. Mol. Cell. Endocrinol. 177, 125–134 (2001).
de la Monte, S. M. & Wands, J. R. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J. Alzheimers Dis. 7, 45–61 (2005).
Frolich, L. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J. Neural Transm. 105, 423–438 (1998).
Zhao, W. Q. et al. Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Aβ. J. Biol. Chem. 284, 18742–18753 (2009).
Gasparini, L. & Xu, H. Potential roles of insulin and IGF-1 in Alzheimer's disease. Trends Neurosci. 26, 404–406 (2003).
Pedersen, W. A. et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp. Neurol. 199, 265–273 (2006).
Watson, G. S. et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry 13, 950–958 (2005).
Hong, M. & Lee, V. M. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J. Biol. Chem. 272, 19547–19553 (1997).
Lesort, M. & Johnson, G. V. Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience 99, 305–316 (2000).
Cheng, C. M. et al. Tau is hyperphosphorylated in the insulin-like growth factor-I null brain. Endocrinology 146, 5086–5091 (2005).
Schubert, M. et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J. Neurosci. 23, 7084–7092 (2003).
Freude, S. et al. Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes 54, 3343–3348 (2005).
Pearson, L. L., Castle, B. E. & Kehry, M. R. CD40-mediated signaling in monocytic cells: up-regulation of tumor necrosis factor receptor-associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways. Int. Immunol. 13, 273–283 (2001).
Brazil, D. P. & Hemmings, B. A. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci. 26, 657–664 (2001).
Tremblay, M. L. & Giguere, V. Phosphatases at the heart of FoxO metabolic control. Cell Metab. 7, 101–103 (2008).
Hensley, K. et al. p38 kinase is activated in the Alzheimer's disease brain. J. Neurochem. 72, 2053–2058 (1999).
Munoz, L. & Ammit, A. J. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 58, 561–568 (2010).
Kelleher, I., Garwood, C., Hanger, D. P., Anderton, B. H. & Noble, W. Kinase activities increase during the development of tauopathy in htau mice. J. Neurochem. 103, 2256–2267 (2007).
Balaraman, Y., Limaye, A. R., Levey, A. I. & Srinivasan, S. Glycogen synthase kinase 3β and Alzheimer's disease: pathophysiological and therapeutic significance. Cell. Mol. Life Sci. 63, 1226–1235 (2006).
Lee, J. & Kim, M. S. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res. Clin. Pract. 77 (Suppl. 1), S49–S57 (2007).
Clodfelder-Miller, B., De Sarno, P., Zmijewska, A. A., Song, L. & Jope, R. S. Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3. J. Biol. Chem. 280, 39723–39731 (2005).
Phiel, C. J., Wilson, C. A., Lee, V. M. & Klein, P. S. GSK-3α regulates production of Alzheimer's disease amyloid-β peptides. Nature 423, 435–439 (2003).
Noble, W. et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl Acad. Sci. USA 102, 6990–6995 (2005).
Small, G. W. et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 97, 6037–6042 (2000).
Garrido, G. E. et al. Relation between medial temporal atrophy and functional brain activity during memory processing in Alzheimer's disease: a combined MRI and SPECT study. J. Neurol. Neurosurg. Psychiatry 73, 508–516 (2002).
Watson, G. S. & Craft, S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur. J. Pharmacol. 490, 97–113 (2004).
Biessels, G. J., van der Heide, L. P., Kamal, A., Bleys, R. L. & Gispen, W. H. Ageing and diabetes: implications for brain function. Eur. J. Pharmacol. 441, 1–14 (2002).
Hunt, J. V., Dean, R. T. & Wolff, S. P. Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. Biochem. J. 256, 205–212 (1988).
Singh, R., Barden, A., Mori, T. & Beilin, L. Advanced glycation end-products: a review. Diabetologia 44, 129–146 (2001).
Brownlee, M. Advanced protein glycosylation in diabetes and aging. Annu. Rev. Med. 46, 223–234 (1995).
Sasaki, N. et al. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am. J. Pathol. 153, 1149–1155 (1998).
Sasaki, N. et al. Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease. Brain Res. 888, 256–262 (2001).
Ledesma, M. D., Bonay, P., Colaco, C. & Avila, J. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269, 21614–21619 (1994).
Toth, C. et al. Diabetes, leukoencephalopathy and rage. Neurobiol. Dis. 23, 445–461 (2006).
Girones, X. et al. N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease. Free Radic. Biol. Med. 36, 1241–1247 (2004).
Heitner, J. & Dickson, D. Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study. Neurology 49, 1306–1311 (1997).
Russell, J. W. et al. Oxidative injury and neuropathy in diabetes and impaired glucose tolerance. Neurobiol. Dis. 30, 420–429 (2008).
Vincent, A. M., Russell, J. W., Low, P. & Feldman, E. L. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr. Rev. 25, 612–628 (2004).
Giugliano, D., Ceriello, A. & Paolisso, G. Oxidative stress and diabetic vascular complications. Diabetes Care 19, 257–267 (1996).
Pratico, D. & Sung, S. Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease. J. Alzheimers Dis. 6, 171–175 (2004).
Butterfield, D. A. et al. Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res. 1148, 243–248 (2007).
Pratico, D., Uryu, K., Leight, S., Trojanoswki, J. Q. & Lee, V. M. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183–4187 (2001).
Apelt, J., Bigl, M., Wunderlich, P. & Schliebs, R. Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int. J. Dev. Neurosci. 22, 475–484 (2004).
Matsuoka, Y., Picciano, M., La Francois, J. & Duff, K. Fibrillar β-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease. Neuroscience 104, 609–613 (2001).
Resende, R. et al. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic. Biol. Med. 44, 2051–2057 (2008).
Reddy, P. H. & Beal, M. F. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol. Med. 14, 45–53 (2008).
Tan, J. et al. Microglial activation resulting from CD40-CD40L interaction after β-amyloid stimulation. Science 286, 2352–2355 (1999).
van de Ree, M. A., Huisman, M. V., Princen, H. M., Meinders, A. E. & Kluft, C. Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis 166, 129–135 (2003).
Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).
Sly, L. M. et al. Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer's disease. Brain Res. Bull. 56, 581–588 (2001).
Szekely, C. A. et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology 23, 159–169 (2004).
Aisen, P. S. et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819–2826 (2003).
Reines, S. A. et al. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 62, 66–71 (2004).
Schaefer, E. J. et al. Familial apolipoprotein E deficiency. J. Clin. Invest. 78, 1206–1219 (1986).
Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Invest. 92, 883–893 (1993).
Peila, R., Rodriguez, B. L. & Launer, L. J. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu–Asia Aging Study. Diabetes 51, 1256–1262 (2002).
Kuusisto, J. 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 315, 1045–1049 (1997).
Profenno, L. A. & Faraone, S. V. Diabetes and overweight associate with non-APOE4 genotype in an Alzheimer's disease population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 822–829 (2008).
LaDu, M. J. et al. Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269, 23403–23406 (1994).
Belinson, H., Lev, D., Masliah, E. & Michaelson, D. M. Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. J. Neurosci. 28, 4690–4701 (2008).
Brecht, W. J. et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004).
Ulery, P. G. et al. Modulation of β-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. J. Biol. Chem. 275, 7410–7415 (2000).
Yaffe, K. Metabolic syndrome and cognitive decline. Curr. Alzheimer Res. 4, 123–126 (2007).
Harris, M. I. Hypercholesterolemia in diabetes and glucose intolerance in the U. S. population. Diabetes Care 14, 366–374 (1991).
Ishikawa, M. et al. Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity. J. Lipid Res. 49, 2524–2534 (2008).
Sharma, S., Prasanthi, R. P. J., Schommer, E., Feist, G. & Ghribi, O. Hypercholesterolemia-induced Aβ accumulation in rabbit brain is associated with alteration in IGF-1 signaling. Neurobiol. Dis. 32, 426–432 (2008).
Burns, M. P. et al. Co-localization of cholesterol, apolipoprotein E and fibrillar Aβ in amyloid plaques. Brain Res. Mol. Brain Res. 110, 119–125 (2003).
Mori, T. et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J. Neuropathol. Exp. Neurol. 60, 778–785 (2001).
Bjorkhem, I., Heverin, M., Leoni, V., Meaney, S. & Diczfalusy, U. Oxysterols and Alzheimer's disease. Acta Neurol. Scand. Suppl. 185, 43–49 (2006).
Prasanthi, J. R. et al. Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol. Neurodegener. 4, 1 (2009).
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. & Drachman, D. A. Statins and the risk of dementia. Lancet 356, 1627–1631 (2000).
Distl, R., Meske, V. & Ohm, T. G. Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol. 101, 547–554 (2001).
Refolo, L. M. et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7, 321–331 (2000).
Rizzuto, R. et al. Mitochondria as biosensors of calcium microdomains. Cell Calcium 26, 193–199 (1999).
Khachaturian, Z. S. Calcium hypothesis of Alzheimer's disease and brain aging. Ann. NY Acad. Sci. 747, 1–11 (1994).
Kostyuk, E. et al. Diabetes-induced changes in calcium homeostasis and the effects of calcium channel blockers in rat and mice nociceptive neurons. Diabetologia 44, 1302–1309 (2001).
Brustovetsky, N., Brustovetsky, T., Jemmerson, R. & Dubinsky, J. M. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J. Neurochem. 80, 207–218 (2002).
Anandatheerthavarada, H. K., Biswas, G., Robin, M. A. & Avadhani, N. G. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell Biol. 161, 41–54 (2003).
Crouch, P. J. et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1–42 . J. Neurosci. 25, 672–679 (2005).
Blass, J. P. & Gibson, G. E. The role of oxidative abnormalities in the pathophysiology of Alzheimer's disease. Rev. Neurol. (Paris) 147, 513–525 (1991).
Hirai, K. et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21, 3017–3023 (2001).
Murray, F. E., Landsberg, J. P., Williams, R. J., Esiri, M. M. & Watt, F. Elemental analysis of neurofibrillary tangles in Alzheimer's disease using proton-induced X-ray analysis. Ciba Found. Symp. 169, 201–210 (1992).
Nixon, R. A. et al. Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease. Ann. NY Acad. Sci. 747, 77–91 (1994).
McKee, A. C., Kosik, K. S., Kennedy, M. B. & Kowall, N. W. Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase. J. Neuropathol. Exp. Neurol. 49, 49–63 (1990).
Johnson, G. V. et al. Transglutaminase activity is increased in Alzheimer's disease brain. Brain Res. 751, 323–329 (1997).
Querfurth, H. W. & Selkoe, D. J. Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33, 4550–4561 (1994).
Levy, J., Gavin, J. R. 3rd & Sowers, J. R. Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am. J. Med. 96, 260–273 (1994).
Levy, J., Zemel, M. B. & Sowers, J. R. Role of cellular calcium metabolism in abnormal glucose metabolism and diabetic hypertension. Am. J. Med. 87, 7S–16S (1989).
Studer, R. K. & Ganas, L. Effect of diabetes on hormone-stimulated and basal hepatocyte calcium metabolism. Endocrinology 125, 2421–2433 (1989).
Moreira, P. I., Santos, M. S., Sena, C., Seica, R. & Oliveira, C. R. Insulin protects against amyloid β-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol. Dis. 18, 628–637 (2005).
Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).
Ke, Y. D., Delerue, F., Gladbach, A., Gotz, J. & Ittner, L. M. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. PLoS ONE 4, e7917 (2009).
Jolivalt, C. G. et al. Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp. Neurol. 223, 422–431 (2010).
Takeda, S. et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. Proc. Natl Acad. Sci. USA 107, 7036–7041 (2010).
Morrison, C. D. Leptin signaling in brain: A link between nutrition and cognition? Biochim. Biophys. Acta 1792, 401–408 (2009).
Ott, A. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937–1942 (1999).
Brayne, C. et al. Vascular risks and incident dementia: results from a cohort study of the very old. Dement. Geriatr. Cogn. Disord. 9, 175–180 (1998).
Yoshitake, T. et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology 45, 1161–1168 (1995).
Xu, W. L., Qiu, C. X., Wahlin, A., Winblad, B. & Fratiglioni, L. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63, 1181–1186 (2004).
Leibson, C. L. et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am. J. Epidemiol. 145, 301–308 (1997).
Luchsinger, J. A. et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65, 545–551 (2005).
Arvanitakis, Z., Wilson, R. S., Bienias, J. L., Evans, D. A. & Bennett, D. A. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch. Neurol. 61, 661–666 (2004).
The authors greatly appreciate the helpful discussion with Dr. K. A. Sullivan (University of Michigan, Ann Arbor, MI, USA). This work was supported by an Aging Training Grant (NIA T32-AG000114), and grants from the Animal Models of Diabetic Complications Consortium (NIH U01-DK076160), the Taubman Institute and the Program for Neurology Research and Discovery.
The authors declare no competing financial interests.
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Sims-Robinson, C., Kim, B., Rosko, A. et al. How does diabetes accelerate Alzheimer disease pathology?. Nat Rev Neurol 6, 551–559 (2010). https://doi.org/10.1038/nrneurol.2010.130
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