Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Table of Contents
Vol. 30, No. 2, 2010
Issue release date: September 2010
Section title: Original Research Article
Free Access
Dement Geriatr Cogn Disord 2010;30:131–146

Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study

Gold M.c · Alderton C.a · Zvartau-Hind M.a · Egginton S.b · Saunders A.M.d · Irizarry M.c · Craft S.e · Landreth G.f · Linnamägi Ü.g · Sawchak S.c
aNeurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, and bNeurosciences Medicines Development Center, GlaxoSmithKline, Harlow, UK; cNeurosciences Medicines Development Center, GlaxoSmithKline, Research Triangle Park, N.C., dDeane Drug Discovery Institute, Division of Neurology, Duke University Medical Center, Durham, N.C., eGeriatric Research, Education and Clinical Center, VA Puget Sound Health Care System and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Wash., and fDepartment of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; gDepartment of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
email Corresponding Author

Michael Gold, MS, MD

Neurosciences Medicine Development Center


Research Triangle Park, NC (USA)

Tel. +1 919 483 8119, Fax +1 919 315 4687, E-Mail michael.2.gold@gsk.com


  1. Cummings JL: Alzheimer’s disease. N Engl J Med 2004;351:56–67.
  2. Watson GS, Craft S: The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 2003;17:27–45.
  3. Craft S: Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 2007;4:147–152.
  4. Craft S: The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 2009;66:300–305.
  5. Profenno LA, Porsteinsson AP, Faraone SV: Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67:505–512.
  6. Solfrizzi V, Scafato E, Capurso C, et al: Metabolic syndrome, mild cognitive impairment, and progression to dementia: the Italian Longitudinal Study on Aging. Neurobiol Aging 2009, E-pub ahead of print.
  7. Forti P, Pisacane N, Rietti E, et al: Metabolic syndrome and risk of dementia in older adults. J Am Geriatr Soc 2010;58:487–492.
  8. Geroldi C, Frisoni GB, Paolisso G, et al: Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 2005;62:1067–1072.
  9. Bourdel-Marchasson I, Lapre E, Laksir H, Puget E: Insulin resistance, diabetes and cognitive function: consequences for preventative strategies. Diabetes Metab 2010;36:173–181.
  10. Rasgon NL, Kenna HA, Wroolie TE, et al: Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging 2009, E-pub ahead of print.
  11. de Felice FG, Vieira MN, Bomfim TR, et al: Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc Natl Acad Sci USA 2009;106:1971–1976.
  12. Park CR, Seeley RJ, Craft S, Woods SC: Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000;68:509–514.
  13. Craft S, Asthana S, Cook DG, et al: Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003;28:809–822.
  14. Reger MA, Watson GS, Green PS, et al: Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70:440–448.
  15. Balfour JA, Plosker GL: Rosiglitazone. Drugs 1999;57:921–930.
  16. Strum JC, Shehee R, Virley D, et al: Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 2007;11:45–51.
  17. Straus DS, Glass CK: Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 2007;28:551–558.
  18. Ghisletti S, Huang W, Ogawa S, et al: Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPAR-γ. Mol Cell 2007;25:57–70.
  19. Nicolakakis N, Aboulkassim T, Ongali B, et al: Complete rescue of cerebrovascular function in aged Alzheimer’s disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor-γ agonist. J Neurosci 2008;28:9287–9296.
  20. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR: Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006;199:265–273.
  21. Toledo EM, Inestrosa NC: Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer’s disease. Mol Psychiatry 2010;15:272–285, 228.
  22. Watson GS, Cholerton BA, Reger MA, 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 2005;13:950–958.
  23. Risner ME, Saunders AM, Altman JF, et al: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006;6:246–254.
  24. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
  25. Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  26. Román GC, Tatemichi TK, Erkinjuntti T, et al: Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 1993;43:250–260.
    External Resources
  27. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  28. Schneider LS, Olin JT, Doody RS, et al: Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S22–S32.
  29. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314.
  30. Gélinas I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 1999;53:471–481.
  31. GlaxoSmithKline: AVANDIA® prescribing information. Research Triangle Park, GlaxoSmithKline.
  32. Doward LC: The development of the Alzheimer’s Carers’ Quality of Life Instrument (ACQLI). Qual Life Res 1997;6:639.
  33. Wimo A, Wetterholm AL, Mastey V, Winblad B: Evaluation of the healthcare resource utilization and caregiver time in anti-dementia drug trials: a quantitative battery; in Wimo A, Karlsson G, Jonsson B, Winblad B (eds): The Health Economics of Dementia. London, John Wiley & Sons, 1998, pp 465–499.
  34. EuroQol Group: EuroQol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
  35. Lane P: Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat 2008;7:93–106.
  36. Gold M: Study design factors and patient demographics and their effect on the decline of placebo-treated subjects in randomized clinical trials in Alzheimer’s disease. J Clin Psychiatry 2007;68:430–438.
  37. Kreider M, Heise M: Rosiglitazone in the management of older patients with type 2 diabetes mellitus. Int J Clin Pract 2002;56:538–541.
  38. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998;50:136–145.
  39. Burns A, Rossor M, Hecker J, et al: The effects of donepezil in Alzheimer’s disease: results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237–244.
  40. Farlow M, Anand R, Messina J Jr, Hartman R, Veach J: A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2000;44:236–241.
  41. Raskind MA, Peskind ER, Wessel T, Yuan W: Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54:2261–2268.
  42. Wilcock GK, Lilienfeld S, Gaens E: Efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000;321:1445–1449.
  43. Hoyt BD, Massman PJ, Schatschneider C, Cooke N, Doody RS: Individual growth curve analysis of APOE ε4-associated cognitive decline in Alzheimer disease. Arch Neurol 2005;62:454–459.
  44. Frisoni GB, Govoni S, Geroldi C, et al: Gene dose of the ε4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer’s disease. Ann Neurol 1995;37:596–604.
  45. Stern Y, Brandt J, Albert M, et al: The absence of an apolipoprotein ε4 allele is associated with a more aggressive form of Alzheimer’s disease. Ann Neurol 1997;41:615–620.
  46. Irizarry MC, Webb DJ, Bains C, et al: Predictors of placebo group decline in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) in 24-week clinical trials of Alzheimer’s disease. J Alzheimers Dis 2008;14:301–311.
  47. Doraiswamy PM, Krishnan KR, Anand R, et al: Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog Neuropsychopharmacol Biol Psychiatry 2002;26:705–712.
  48. Kurz A, Farlow M, Quarg P, Spiegel R: Disease stage in Alzheimer disease and treatment effects of rivastigmine. Alzheimer Dis Assoc Disord 2004;18:123–128.
  49. Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al: Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Curr Alzheimer Res 2009, E-pub ahead of print.
  50. Cukierman-Yaffee T: The relationship between dysglycemia and cognitive dysfunction. Curr Opin Investig Drugs 2009;10:70–74.
  51. 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 Neurosci 1993;107:926–940.
  52. Domínguez RO, Marschoff ER, Guareschi EM, et al: Insulin, glucose and glycated hemoglobin in Alzheimer’s and vascular dementia with and without superimposed type II diabetes mellitus condition. J Neural Transm 2008;115:77–84.
  53. Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T: Collecting duct-specific deletion of peroxisome proliferator-activated receptor-γ blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci USA 2005;102:9406–9411.
  54. Yang T, Soodvilai S: Renal and vascular mechanisms of thiazolidinedione-induced fluid retention. PPAR Res 2008;2008:943614.
    External Resources
  55. Karalliedde J, Buckingham RE: Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. Drug Saf 2007;30:741–753.
  56. Cortes F, Nourhashémi F, Guérin O, et al: Prognosis of Alzheimer’s disease today: a two-year prospective study in 686 patients from the REAL-FR Study. Alzheimers Dement 2008;4:22–29.
  57. Schneider LS, Sano M: Current Alzheimer’s disease clinical trials: methods and placebo outcomes. Alzheimers Dement 2009;5:388–397.
  58. Gendelman HE: Biomarkers, laboratory, and animal models for the design and development of adjunctive therapies for HIV-1 dementia and other neuroinflammatory disorders. J Neuroimmune Pharmacol 2007;2:8–13.
  59. Bauer B, Hartz AM, Miller DS: Tumor necrosis factor-α and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. Mol Pharmacol 2007;71:667–675.
  60. Yu C, Argyropoulos G, Zhang Y, Kastin AJ, Hsuchou H, Pan W: Neuroinflammation activates Mdr1b efflux transport through NF-ĸB: promoter analysis in BBB endothelia. Cell Physiol Biochem 2008;22:745–756.