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Academia Mexicana de Neurología, A.C.

2013, Número 4

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Rev Mex Neuroci 2013; 14 (4)


Estado actual de las terapias modificadoras en enfermedad de Alzheimer

Carrillo-Mora P, Mena-Barranco FJ, Navarrete-Báez H

Idioma: Español
Referencias bibliográficas: 101
Paginas: 201-214
Archivo PDF: 257.20 Kb.


RESUMEN

Todas las estimaciones epidemiológicas a nivel mundial coinciden en que en las próximas décadas se espera un incremento importante en los casos de enfermedad de Alzheimer (EA). Por este motivo, a nivel mundial hay un impulso sin precedentes en la investigación tanto básica como clínica sobre nuevas alternativas terapéuticas para la EA que no sólo posean un efecto sintomático, sino que realmente logren modificar significativamente el curso de la enfermedad (terapias modificadoras). Actualmente una impresionante variedad de blancos terapéuticos están siendo explorados (algunos de ellos incluso ya en el ámbito clínico), todos ellos basados en la modificación de alguno de los factores fisiopatológicos implicados en la EA: inhibidores y moduladores de gamma secretasa, activadores de alfa secretasa, inmunoterapia activa y pasiva contra Aβ y tau, inhibidores de la agregación de Aβ y tau, inhibidores de la fosforilación de tau, antioxidantes, anti-inflamatorios, estatinas, terapia génica, etc. En el presente artículo se realiza una revisión acerca del estado actual que guardan las terapias modificadoras de la enfermedad en EA según su blanco terapéutico. Lamentablemente los resultados de la gran mayoría de los estudios clínicos han arrojado resultados negativos por dos principales causas: la severidad de los efectos colaterales y la falta de eficacia significativa o ambas. En este momento se están desarrollando fármacos que a nivel experimental han demostrado efectos prometedores pero faltará ver sus efectos clínicos y su seguridad a largo plazo.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. Lancet 2009; 374: 1196-208.

  2. Mayeux R, Stern Y. Epidemiology of Alzheimer Disease. Cold Spring Harb Perspect Med 2012; 2: a006239.

  3. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: 2112-17.

  4. Alvarado-Esquivel C, Hernández-Alvarado AB, Tapia-Rodríguez RO, Guerrero-Iturbe A, Rodríguez-Corral K, Martínez SE. Prevalence of dementia and Alzheimer’s disease in elders of nursing homes and a senior center of Durango City, Mexico. BMC Psychiatry 2004; 4: 3.

  5. Mejía-Arango S, Miguel-Jaimes A, Villa A, Ruiz-Arregui L, Gutiérrez-Robledo LM. Deterioro cognoscitivo y factores asociados en adultos mayores en México. Salud Publica Mex 2007; 49(Supl. 4): S475-S481.

  6. Lliebre-Rodriguez JJ, Ferri CP, Acosta D, Guerra M, Huang Y, Jacob KS, et al. Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey. Lancet 2008; 372: 464-74.

  7. Vellas B, Andrieu S, Sampaio C, Wilcock G, Disease-modifying trials in Alzheimer’s disease: a European task force consensus. Lancet Neurol 2007; 6: 56-62.

  8. Cummings JL. Defining and labeling disease-modifying treatments for Alzheimer’s Disease. Alzheimer & Dementia 2009; 5: 406-18.

  9. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharm Sci 1991; 12: 383-8.

  10. Hardy J, Higgins GA, Alzheimer’s disease: the amyloid cascade hypothesis, Science 1992; 286: 184-5.

  11. Eckman CB, Eckman EA. An update on amyloid hypothesis. Neurol Clin 2007; 25: 669-82.

  12. Perl DP. Neuropathology of Alzheimer Disease. Mount Sinai J Med 2010; 77: 32-42.

  13. Vetrivel KS, Thinakaran G. Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments. Neurology 2006; 66 (Suppl. 1): S69-S73.

  14. Postina G. A Closer look at α-secretase. Curr Alzheimer Res 2008; 5: 179-86.

  15. Nathalie P, Jean-Noel O. Procesing of amyloid precursor protein and amyloid peptide neurotoxicity. Curr Alz Res 2008; 5: 92-9.

  16. Canevari L, Clark JB, Bates TE. β-amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Letters 1999; 457: 131-4.

  17. Lin H, Bhatia R, Lal R. Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology. FASEB J 2001; 15: 2433-44.

  18. Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velazquez M, Acosta- Martinez JP, Ortiz GG. Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo. J Neuroimmunol 2004; 150: 20-8.

  19. Butterfield DA, Reed T, Newman SF, Sultana R. Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Rad Biol Med 2007; 43: 658-77.

  20. Parameshwaran K, Dhanasekaran M, Suppiramaniam V. Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 2008; 210: 7-13.

  21. Puzzo D, Privitera L, Fa’ M, Staniszewski A, Hashimoto G, Aziz F, Sakurai M, et al. Endogenous amyloid-b is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 2011; 69: 819-30.

  22. Kern A, Behl C. The unsolved relationship of brain aging and late-onset Alzheimer disease. Biochim Biophys Acta 2009; 1790: 1124-32.

  23. Golde TE, Schneider LS, Koo EH. Anti-Aβ therapeutics in Alzheimer’s Disease: The need for a paradigm shift. Neuron 2011; 69: 203-13.

  24. Maccioni RB, Farias G, Morales I, Navarrete L. The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 2010; 41: 226-31.

  25. Avila J, Lucas JJ, Pérez M, Hernández F. Role of Tau Protein in both Physiological and Pathological Conditions. Physiol Rev 2004; 84: 361-84.

  26. Ittner LM, Gotz J. Amyloid-β and tau-a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 2011; 12: 67-72.

  27. Nelson PT, Braak H, Markesbery WR. Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship. J Neuropathol Exp Neurol 2009; 68: 1-14.

  28. Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, et al. Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau. PLoS ONE 2007; 2(6): e536. doi:10.1371/journal.pone.0000536.

  29. Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease- A brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2012; 2: a006346.

  30. Vlad SC, Miller DR, KowallNW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008; 70: 1672-7.

  31. Katsel P, Tan W, Haroutunian V. Gain in brain immunity in the oldestold differentiates cognitively normal from demented individuals. PLoS One 2009; 4: e7642.

  32. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25: 9275-84.

  33. Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma PL. Excitotoxicity: Bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol 2013; 698: 6-18.

  34. Danyzs W, Parsons CG. The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 2003; 18: S23-S32.

  35. Frisardi V, Solfrizzi V, Imbimbo PB, Capurso C, D’Introno A, Colacicco AM, et al. Towards Disease-Modifying Treatment of Alzheimer’s Disease: Drugs Targeting β-Amyloid. Curr Alzheimer Res 2010; 7: 40-55.

  36. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, et al. Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 2005; 28: 126-32.

  37. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 2007; 30: 317-25.

  38. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch Neurol 2008; 65: 1031-8.

  39. Cummings J. What Can Be Inferred from the Interruption of the Semagacestat Trial for Treatment of Alzheimer’s Disease? Biol Psychiatry 2010; 68: 876-8.

  40. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease; a randomised phase II trial. Lancet Neurol 2008; 7: 483-93.

  41. Borgegard T, Juréus A, Olsson F, Rosqvist S, Sabirsh A, Rotticci D, et al. First and second generation g-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. J Biol Chem. 2012; 287: 11810-9.

  42. Ghosh AK, Gemma S, Tang J. Beta-Secretase as a therapeutic target for Alzheimer’s disease. Neurotherapeutics 2008; 5: 399-408.

  43. Strobel G. Keystone Drug News: CoMentis BACE Inhibitor Debuts 2008. Disponible en: http://www.alzforum.org/new/detail.asp?id=1790

  44. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9: 1520-5.

  45. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006; 314: 664-6.

  46. Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000; 48: 913-18.

  47. Galimberti D, Ghezzi L, Scarpini E. Immunotherapy against amyloid pathology in Alzheimer’s disease. J Neurol Sci 2013 doi.org/10.1016/j.jns.2012.12.013.

  48. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11: 597-604.

  49. Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, et al. Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer’s Disease: Prelude to a Clinical Trial. J Neurosci 2013; 33: 4923-34.

  50. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000; 6: 916-19.

  51. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2001; 98: 8850-5.

  52. Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011; 77: 1253-62.

  53. Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012; 11: 241-9.

  54. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid- β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 2010; 9: 363-72.

  55. Roher AE, Cribbs DH, Kim RC, Maarouf CL, Whiteside CM, et al. Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti Amyloid Immunotherapy. PLoS ONE 2013; 8(3): e59735.

  56. Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012; 8: 261-71.

  57. Shimada M, Abe S, Takahashi T, Shiozaki K, Okuda M, et al. Prophylaxis and Treatment of Alzheimer’s Disease by Delivery of an Adeno-Associated Virus Encoding a Monoclonal Antibody Targeting the Amyloid Beta Protein. PLoS ONE 2013; 8(3): e57606

  58. Dodel RC, Du Y, Depboylu C, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer‘s disease. J Neurol Neurosurg Psychiatry 2004; 75: 1472-7.

  59. Relkin NR, Szabo P, Adamiak B, et al. 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 2009; 30: 1728-36.

  60. Weksler M, Szabo P, Relkin N. IVIG therapy of mild to moderate Alzheimer’s disease patients showed significant benefits as measured by neuroimaging and neuropsychological testing in a phase II, randomized, double blind placebo controlled clinical study. Gerontologist 2010; 50: 449-50.

  61. Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, et al. lntravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomised, double-blind, placebocontrolled, dose-finding trial. Lancet Neurol 2013; 12: 233-43.

  62. Golde TE, Petrucelli L, Lewis J. Targeting Aβ and tau in Alzheimer’s disease, an early interim report. Exp Neurol 2010; 223: 252-66.

  63. Bush AI, Tanzi RE. Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 2008; 5: 421-32.

  64. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008; 8: 779-86.

  65. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73: 2061-70.

  66. Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a taupathy model. Proc Natl Acad Sci USA 2005; 102: 227-31.

  67. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer’s-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 2012; 32: 3601-11.

  68. Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci 2010; 30: 13861-6.

  69. Gold M, Lorenzl S, Stewart AJ, Morimoto BH, Williams DR, Gozes I. Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy. Neuropsychiatry Dis Treat 2012; 8: 85-93.

  70. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challengefor neurodegenerative disease. Trends Mol Med 2009; 15: 112-19.

  71. Pei JJ, Grundke-Iqbal I, Iqbal K, Bogdanovic N, Winblad B, Cowburn RF. Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer’s disease neurofibrillary degeneration. Brain Res 1998; 797: 267-77.

  72. Kremer A, Louis JV, Jaworski T, Van Leuven F. GSK3 and Alzheimer’s disease: facts and fiction. Front Mol Neurosci 2011; 4: 17.

  73. Hurtado DE, Molina-Porcel L, Carroll JC, Macdonald C, Aboagye AK, Trojanowski JQ, et al. Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer’s disease. J Neurosci 2012; 32: 7392-402.

  74. Engel T, Goñi-Oliver P, Lucas JJ, Avila J, Hernández F. Chronic lithium administration to FTDP-17 tau and GSK-3 beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 2006; 99: 1445-55.

  75. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011; 198: 351-6.

  76. Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry 2008; 23: 704-11.

  77. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, et al. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009; 70: 922-31

  78. Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 1995; 65: 732-8.

  79. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Liu F. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 2005; 22: 1942-50.

  80. Choban MO, Khatoon S, Iqbal IG, Iqbal K. Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by memantine. FEBS Lett 2006; 580: 3973-9.

  81. Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Merkle RK, Gong CX. Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett 2002; 512: 101-6.

  82. Wischik C, Staff R. Challenges in the conduct of disease-modifyng trials in AD: practical experience from a phase 2 trial of tau-aggregation inhibitor therapy. J Nutr Health Aging 2009; 13: 367-9.

  83. Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 2006; 15: 433-42.

  84. Chambraud B, Sardin E, Giustiniani J, Dounane O, Schumacher M, Goedert M, et al. A role for FKBP52 in tau protein function. Proc Natl Acad Sci USA 2010; 107: 2658-63.

  85. Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 2012; 135: 2169-77.

  86. Chin J, Palop JJ, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 2005; 25: 9694-703.

  87. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010; 68: 1067-81.

  88. Sigurdsson EM. Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J Alzheimers Dis 2008; 15: 157-68.

  89. Rogers J. Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993; 43: 1609-11.

  90. Vellas B, Aisen P, Sampaio C, Carrillo M, Scheltens P, Scherrer B. et al. Prevention trials in Alzheimer’s disease: an EU-US task force report. Prog Neurobiol 2011; 95: 594-600.

  91. Tracey D, Klareskog L, Sasso EH,Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action:a comprehensive review. Pharmacol Ther 2008; 117: 244-79.

  92. Tobnick E. Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease. Curr Alzh Res 2012; 9: 99-109.

  93. Tobinick, E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2010; 10: 985-1002.

  94. Griffin, W. Inflammation and neurodegenerative diseases. Am J Clin Nutr 2006; 3(Suppl.): 470-4.

  95. Hubbard, B. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Science 2013; 339, 6124: 1216-19.

  96. Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen TY, et al. Identification of brain-targeted bioactive dietary quercetin-3-Oglucuronide as a novel intervention for Alzheimer’s disease. FASEB J 2013; 27: 769-81.

  97. Lövdén M, Xu W, Wang HX. Lifestyle change and the prevention of cognitive decline and dementia: what is the evidence? Curr Opin Psychiatry 2013; 26: 239-43.

  98. Schindler, T. PET scans reveal hormone replacement therapy may be beneficial for menopausal women. Society of Nuclear Medicine and Molecular Imgaging. 2008 Annual Metting. June 16, 2008.

  99. Craft S, Baker L, Montine TJ, Minoshima S, Watson S, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment A Pilot Clinical Trial. JAMA Neurol 2012; 69: 29-38.

  100. 100.Kandiah N, Feldman HH. Therapautic potential of statins in Alzheimer´s disease. J Neurol Sci 2009; 283: 230-4.

  101. 101.Feldman HH, Doody RS, Kivipelto M, Sparks L, Waters DD, Jones RW, et al Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease. Neurology 2010; 74: 956-64.




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