Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?

Epidemiological and basic science evidence suggest a possible shared pathophysiology between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has even been hypothesized that AD might be 'type 3 diabetes'. The present review summarizes some of the evidence for the possible link, putative biochemical pathways and ongoing clinical trials of antidiabetic drugs in AD patients. The primary and review literature were searched for articles published in peer-reviewed sources that were related to a putative connection between T2DM and AD. In addition, public sources of clinical trials were searched for the relevant information regarding the testing of antidiabetic drugs in AD patients. The evidence for a connection between T2DM and AD is based upon a variety of diverse studies, but definitive biochemical mechanisms remain unknown. Additional study is needed to prove the existence or the extent of a link between T2DM and AD, but sufficient evidence exists to warrant further study. Presently, AD patients might benefit from treatment with pharmacotherapy currently used to treat T2DM and clinical trials of such therapy are currently underway.

[1]  S. Edland Insulin-degrading enzyme, apolipoprotein E, and Alzheimer’s disease , 2007, Journal of Molecular Neuroscience.

[2]  J. Kaprio,et al.  Environmental differences in twin pairs discordant for Alzheimer’s disease , 1998, Journal of neurology, neurosurgery, and psychiatry.

[3]  L. Lue,et al.  Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures , 2001, Neurobiology of Aging.

[4]  Nicholas J. Wareham,et al.  Glycated Hemoglobin and Risk of Stroke in People Without Known Diabetes in the European Prospective Investigation Into Cancer (EPIC)–Norfolk Prospective Population Study: A Threshold Relationship? , 2007, Stroke.

[5]  S. Woods,et al.  Genetically obese Zucker rats have abnormally low brain insulin content. , 1985, Life sciences.

[6]  R. Stelzmann,et al.  An english translation of alzheimer's 1907 paper, “über eine eigenartige erkankung der hirnrinde” , 1995, Clinical anatomy.

[7]  R. Martins,et al.  Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease , 2009, Journal of neurochemistry.

[8]  H. Kaneto,et al.  Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. , 2007, Current molecular medicine.

[9]  C. Clark,et al.  Earlier onset of Alzheimer disease symptoms in latino individuals compared with anglo individuals. , 2005, Archives of neurology.

[10]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[11]  S. Yamagishi,et al.  Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer's disease. , 2008, Current pharmaceutical design.

[12]  A. Drash,et al.  Cognitive deficits in adolescents who developed diabetes early in life. , 1985, Pediatrics.

[13]  G. Werther,et al.  Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. , 1987, Endocrinology.

[14]  S. Davis,et al.  Signalling mechanisms mediated by the phosphoinositide 3‐kinase/Akt cascade in synaptic plasticity and memory in the rat , 2006, The European journal of neuroscience.

[15]  P. Greengard,et al.  Role of Phosphorylation of Alzheimer’s Amyloid Precursor Protein during Neuronal Differentiation , 1999, The Journal of Neuroscience.

[16]  R. Pratley,et al.  Review: Pre-diabetes: clinical relevance and therapeutic approach , 2007 .

[17]  S. Woods,et al.  Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. , 2000, Diabetes.

[18]  Suzanne Craft,et al.  Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. , 2007, Current Alzheimer research.

[19]  J. Searcy,et al.  Distinct modulation of voltage‐gated and ligand‐gated Ca2+ currents by PPAR‐γ agonists in cultured hippocampal neurons , 2009, Journal of neurochemistry.

[20]  O. Wiklund,et al.  How can we prevent cardiovascular disease in diabetes , 2007, Journal of internal medicine.

[21]  J. Pickup,et al.  NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X , 1997, Diabetologia.

[22]  D. Accili,et al.  Mechanisms of hormone resistance: lessons from insulin‐resistant patients , 1994, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[23]  H. Hanyu,et al.  Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease , 2011, Neurobiology of Aging.

[24]  R. Raffa,et al.  Potential novel targets for Alzheimer pharmacotherapy: I. Secretases , 2002, Journal of clinical pharmacy and therapeutics.

[25]  Michael W. Schwartz,et al.  Evidence of Cosecretion of Islet Amyloid Polypeptide and Insulin by β-Cells , 1990, Diabetes.

[26]  M. Brownstein,et al.  Insulin receptors are widely distributed in the central nervous system of the rat , 1978, Nature.

[27]  P. S. St George-Hyslop,et al.  gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in? , 2002, Nature reviews. Neuroscience.

[28]  G. Rebeck,et al.  APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome , 1999, Neurology.

[29]  P. Low,et al.  Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. , 2003, Diabetes.

[30]  Jesús Avila,et al.  Glycogen synthase kinase 3: a drug target for CNS therapies , 2004, Journal of neurochemistry.

[31]  P. Wilson,et al.  Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. , 1987, Journal of lipid research.

[32]  J. Berger,et al.  The mechanisms of action of PPARs. , 2002, Annual review of medicine.

[33]  Joseph L Evans,et al.  Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. , 2002, Endocrine reviews.

[34]  J. Wands,et al.  Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. , 2005, Journal of Alzheimer's disease : JAD.

[35]  M. Orth,et al.  Mitochondria and degenerative disorders. , 2001, American journal of medical genetics.

[36]  E. Harlow Retinoblastoma. For our eyes only. , 1992, Nature.

[37]  D. Selkoe,et al.  Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[38]  B. Doble,et al.  Role of Glycogen Synthase Kinase-3 in Cell Fate and Epithelial-Mesenchymal Transitions , 2007, Cells Tissues Organs.

[39]  M. Hayden,et al.  The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease* , 2005, Journal of Biological Chemistry.

[40]  G. Wilcock,et al.  The metabolic syndrome and Alzheimer disease. , 2007, Archives of neurology.

[41]  H. Werner,et al.  Developmental Regulation of the Insulin and Insulin-Like Growth Factor Receptors in the Central Nervous System , 1993 .

[42]  I. Deary,et al.  Cognition and diabetes: a lifespan perspective , 2008, The Lancet Neurology.

[43]  D. Mozaffarian,et al.  Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. , 2009, Archives of internal medicine.

[44]  K. Weisgraber,et al.  Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils. , 2006, Journal of molecular biology.

[45]  R. Mahley,et al.  Plasma lipoproteins: apolipoprotein structure and function. , 1984, Journal of lipid research.

[46]  S. Yamagishi,et al.  Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo. , 2004, Medical hypotheses.

[47]  D. Bredt Endogenous nitric oxide synthesis: biological functions and pathophysiology. , 1999, Free radical research.

[48]  W. Banks,et al.  Effect of Diabetes Mellitus on the Permeability of the Blood–Brain Barrier to Insulin , 1997, Peptides.

[49]  R. Schmidt,et al.  Early inflammation and dementia: A 25‐year follow‐up of the Honolulu‐Asia aging study , 2002, Annals of neurology.

[50]  A Hofman,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[51]  J. Rogers,et al.  A Perspective on Inflammation in Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[52]  M. Reger,et al.  Intranasal insulin improves cognition and modulates beta-amyloid in early AD. , 2008, Neurology.

[53]  Deborah Gustafson,et al.  An 18-year follow-up of overweight and risk of Alzheimer disease. , 2003, Archives of internal medicine.

[54]  R. Swerdlow,et al.  A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. , 2004, Medical hypotheses.

[55]  R. Sandyk,et al.  New vistas in chronic schizophrenia. , 1988, The International journal of neuroscience.

[56]  T. Pawson,et al.  Behavioral / Systems / Cognitive Hippocampal Synaptic Modulation by the Phosphotyrosine Adapter Protein ShcC / N-Shc via Interaction with the NMDA Receptor , 2005 .

[57]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[58]  B. Frangione,et al.  Isolation and Partial Characterization of Neurofibrillary Tangles and Amyloid Plaque Core in Alzheimer's Disease: Immunohistological Studies , 1986, Journal of neuropathology and experimental neurology.

[59]  P. Box Increased cortical atrophy in patients with Alzheimer’s disease and type 2 diabetes mellitus , 2006 .

[60]  A. Astell,et al.  Molecular connexions between dementia and diabetes , 2007, Neuroscience & Biobehavioral Reviews.

[61]  R. G. Thorne,et al.  Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration , 2004, Neuroscience.

[62]  H. Hanyu,et al.  PIOGLITAZONE IMPROVED COGNITION IN A PILOT STUDY ON PATIENTS WITH ALZHEIMER'S DISEASE AND MILD COGNITIVE IMPAIRMENT WITH DIABETES MELLITUS , 2009, Journal of the American Geriatrics Society.

[63]  J. Bauer,et al.  The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimer's disease , 1996, Behavioural Brain Research.

[64]  A. Meinders,et al.  Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. , 2003, Atherosclerosis.

[65]  G. Landreth,et al.  The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer's disease: therapeutic implications. , 2008, CNS drugs.

[66]  P. Gebicke-haerter,et al.  Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains , 1999 .

[67]  Michael S. Wolfe Secretase Targets for Alzheimer′s Disease: Identification and Therapeutic Potential , 2001 .

[68]  E. Harlow For our eyes only , 1992, Nature.

[69]  K. Jellinger,et al.  Intra vitam lumbar and post mortem ventricular cerebrospinal fluid immunoreactive interleukin‐6 in Alzheimer's disease patients , 2001, Acta neurologica Scandinavica.

[70]  Xi Chen,et al.  PI3 kinase signaling is required for retrieval and extinction of contextual memory , 2005, Nature Neuroscience.

[71]  G. Schellenberg,et al.  Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype , 2006, Neurobiology of Aging.

[72]  Marja-Riitta Taskinen Diabetic dyslipidemia. , 2002, Atherosclerosis. Supplements.

[73]  G. Schellenberg,et al.  Dementia and Alzheimer disease incidence: a prospective cohort study. , 2002, Archives of neurology.

[74]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[75]  D. Bennett,et al.  Alzheimer disease in the US population: prevalence estimates using the 2000 census. , 2003, Archives of neurology.

[76]  M. Ferrari,et al.  Migraine as a risk factor for subclinical brain lesions. , 2004, JAMA.

[77]  D. Sax,et al.  Increased frequency of diabetes mellitus in patients with Huntington's chorea. , 1972, Lancet.

[78]  Sangram S. Sisodia,et al.  γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in? , 2002, Nature Reviews Neuroscience.

[79]  L. Waite,et al.  Anti-inflammatory drugs protect against Alzheimer disease at low doses. , 2000, Archives of neurology.

[80]  A. Hofman,et al.  Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. , 2004, Archives of neurology.

[81]  Melonie P. Heron,et al.  Deaths: preliminary data for 2004. , 2006, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[82]  W. Soeller,et al.  Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[83]  R. Castellani,et al.  Alzheimer disease. , 2010, Disease-a-month : DM.

[84]  S. Woods,et al.  Insulin and the blood-brain barrier. , 2003, Current pharmaceutical design.

[85]  D. Dias-Santagata,et al.  Oxidative stress mediates tau-induced neurodegeneration in Drosophila. , 2007, The Journal of clinical investigation.

[86]  S. Craft,et al.  The Role of Insulin Resistance in the Pathogenesis of Alzheimer’s Disease , 2003, CNS drugs.

[87]  J. Hardy,et al.  Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. , 1996, Nature medicine.

[88]  P. Riederer,et al.  Alzheimer's disease – synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts , 1998, Journal of Neural Transmission.

[89]  A. Moses,et al.  Interactions of insulin-like growth factors I and II and multiplication-stimulating activity with receptors and serum carrier proteins. , 1980, Endocrinology.

[90]  G. Hotamisligil,et al.  Inflammatory pathways and insulin action , 2003, International Journal of Obesity.

[91]  T. Kadowaki,et al.  Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[92]  W. Han,et al.  Linking type 2 diabetes and Alzheimer's disease , 2010, Proceedings of the National Academy of Sciences.

[93]  Xiongwei Zhu,et al.  c‐Jun phosphorylation in Alzheimer disease , 2007, Journal of neuroscience research.

[94]  M. Wadman Diabetes drug woes spell trouble for the entire drug family , 2010, Nature Medicine.

[95]  T. Imaizumi,et al.  Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. , 2003, International journal of clinical pharmacology research.

[96]  V. Chandra,et al.  Conditions associated with Alzheimerʼs disease at death: case-control study , 1987 .

[97]  G. Landreth,et al.  Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[98]  J. Hardman,et al.  Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas , 2001 .

[99]  E. Masliah,et al.  Reduced IGF-1 Signaling Delays Age-Associated Proteotoxicity in Mice , 2010, Cell.

[100]  P. Mehta,et al.  Intranasal insulin improves cognition and modulates β-amyloid in early AD , 2008, Neurology.

[101]  R. Pratley,et al.  Pre-diabetes: clinical relevance and therapeutic approach , 2007 .

[102]  L. Morelli,et al.  Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease. , 2009, Current pharmaceutical design.

[103]  Hiroshi Kimura,et al.  Insulin receptor mRNA in the substantia nigra in Parkinson's disease , 1996, Neuroscience Letters.

[104]  P. Freychet,et al.  Insulin receptors and insulin actions in the nervous system , 2000, Diabetes/metabolism research and reviews.

[105]  L. Launer,et al.  Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. , 2002, Diabetes.

[106]  Christian Hölscher,et al.  Common pathological processes in Alzheimer disease and type 2 diabetes: A review , 2007, Brain Research Reviews.

[107]  C. Hölscher Development of Beta-Amyloid-induced Neurodegeneration in Alzheimer's Disease and Novel Neuroprotective Strategies , 2005, Reviews in the neurosciences.

[108]  J. Berger,et al.  PPARs: therapeutic targets for metabolic disease. , 2005, Trends in pharmacological sciences.

[109]  Giuseppe Remuzzi,et al.  Nephropathy in Patients with Type 2 Diabetes , 2002 .

[110]  A. Hofman,et al.  Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. , 2001, The Journal of clinical endocrinology and metabolism.

[111]  Ryuichi Morishita,et al.  Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes , 2010, Proceedings of the National Academy of Sciences.

[112]  M. Wadman Avandia outcome may signal change in epidemiologists' sway , 2010, Nature Medicine.

[113]  Luigi Ferrucci,et al.  Association of adiposity status and changes in early to mid-adulthood with incidence of Alzheimer's disease. , 2008, American journal of epidemiology.

[114]  Hong Qing,et al.  Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes , 2010, Neurobiology of Aging.

[115]  A. Smit,et al.  Towards Understanding the Role of Insulin in the Brain: Lessons from Insulin-related Signaling Systems in the Invertebrate Brain , 1998, Progress in Neurobiology.

[116]  D L Alkon,et al.  Insulin and cholesterol pathways in neuronal function, memory and neurodegeneration. , 2005, Biochemical Society transactions.

[117]  I. Kanazawa,et al.  JNK activation is associated with intracellular beta-amyloid accumulation. , 2000, Brain research. Molecular brain research.

[118]  Mark A Pereira,et al.  Effect of a Lifestyle Intervention on Change in Cardiorespiratory Fitness in Adults with Type 2 Diabetes: Results from the Look AHEAD Study , 2008, International Journal of Obesity.

[119]  K. Jellinger,et al.  Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease , 1998, Journal of Neural Transmission.

[120]  Tamara B Harris,et al.  Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. , 2005, Archives of internal medicine.

[121]  A D Roses,et al.  Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease , 2006, The Pharmacogenomics Journal.

[122]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[123]  R. Petersen Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[124]  Y. Zhong,et al.  PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila , 2010, Proceedings of the National Academy of Sciences.

[125]  G. Wörtwein,et al.  Behavioral symptoms in adult rats after postnatal l-nitro-arginine , 1997, International Journal of Developmental Neuroscience.

[126]  Hilkka Soininen,et al.  Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. , 2005, Archives of neurology.

[127]  I. Kanazawa,et al.  JNK activation is associated with intracellular β-amyloid accumulation , 2000 .

[128]  N. Herrmann,et al.  Review: Therapy for Alzheimer's disease: how effective are current treatments? , 2009, Therapeutic advances in neurological disorders.

[129]  S. Lovestone,et al.  Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice , 2009, Biochemical and biophysical research communications.

[130]  S. Yamagishi,et al.  Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. , 2007, Current pharmaceutical design.

[131]  T. Montine,et al.  Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking , 2009, Annals of neurology.

[132]  B. Winblad,et al.  Insulin-like growth factor 1 (IGF-1) receptors in the human brain: quantitative autoradiographic localization , 1989, Brain Research.

[133]  J. Laditka,et al.  P3-132 Epidemiology of Alzheimer's disease: race effects, area variation, and clustering , 2004, Neurobiology of Aging.

[134]  C. Ackerley,et al.  Recruitment of functional GABAA receptors to postsynaptic domains by insulin , 1997, Nature.

[135]  V. Calabrese,et al.  Mitochondrial Involvement in Brain Function and Dysfunction: Relevance to Aging, Neurodegenerative Disorders and Longevity , 2001, Neurochemical Research.

[136]  G. Landreth,et al.  The Role of Peroxisome Proliferator-Activated Receptor-γ PPARγ) in Alzheimer’s Disease , 2012 .

[137]  M. Reger,et al.  Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. , 2005, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[138]  Christina A. Wilson,et al.  GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. , 2003, Nature.

[139]  A. Mooradian Central nervous system complications of diabetes mellitus — a perspective from the blood–brain barrier , 1997, Brain Research Reviews.

[140]  E. Masliah,et al.  Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice , 2010, Experimental Neurology.

[141]  G. Landreth,et al.  Inflammatory Mechanisms in Alzheimer's Disease: Inhibition of β-Amyloid-Stimulated Proinflammatory Responses and Neurotoxicity by PPARγ Agonists , 2000, The Journal of Neuroscience.

[142]  J. Wands,et al.  Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? , 2005, Journal of Alzheimer's disease : JAD.

[143]  M. Norton,et al.  Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists , 2000, Neurology.

[144]  R. J. Doerksen,et al.  Probing the physicochemical and structural requirements for glycogen synthase kinase-3alpha inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides. , 2006, Bioorganic & medicinal chemistry.

[145]  伸二 鍵本 おさえておきたい 糖尿病の海外文献 ●文献●Depression and advanced complications of diabetes: a prospective cohort study. うつと糖尿病進行合併症:前向きコホート研究 , 2010 .

[146]  Jan Born,et al.  Intranasal insulin improves memory in humans , 2004, Psychoneuroendocrinology.

[147]  P. Moreira,et al.  Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure. , 2003, Diabetes.

[148]  Giuseppe Remuzzi,et al.  Clinical practice. Nephropathy in patients with type 2 diabetes. , 2002, The New England journal of medicine.

[149]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[150]  Ronald C Petersen,et al.  Increased risk of type 2 diabetes in Alzheimer disease. , 2004, Diabetes.

[151]  D. Porte,et al.  Localization of insulin receptor mRNA in rat brain by in situ hybridization. , 1990, Endocrinology.

[152]  R. Green,et al.  Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. , 2006, Archives of neurology.

[153]  G. Drewes MARKing tau for tangles and toxicity. , 2004, Trends in biochemical sciences.

[154]  G. Waeber,et al.  Role of the JNK-interacting protein 1/islet brain 1 in cell degeneration in Alzheimer disease and diabetes , 2009, Brain Research Bulletin.

[155]  Zina Kroner,et al.  The relationship between Alzheimer's disease and diabetes: Type 3 diabetes? , 2009, Alternative medicine review : a journal of clinical therapeutic.

[156]  R. Martins,et al.  ReviewGenetics, lifestyle and the roles of amyloid β and oxidative stress in Alzheimer’s disease , 2003, Annals of human biology.

[157]  S. Bolesta,et al.  Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. , 2000, Clinical therapeutics.

[158]  C. Pert,et al.  Autoradiographic localization of insulin receptors in rat brain: Prominence in olfactory and limbic areas , 1986, Neuroscience.

[159]  G. Perry,et al.  Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[160]  Marc Verny,et al.  [Survival after initial diagnosis of Alzheimer disease]. , 2005, Psychologie & neuropsychiatrie du vieillissement.

[161]  P. Moreira,et al.  Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes , 2007, Journal of the Neurological Sciences.

[162]  N. Durany,et al.  Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus , 2010, Neurobiology of Disease.

[163]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.