Understanding and Treating Alzheimer’s Disease

  • Umesh Kumar
  • Alexander Roland
  • Stephen A. Burbidge


Alzheimer’s disease (AD) remains one of the most disabling health conditions in elderly population worldwide. The socio-economic burden of the disease is likely to increase due to increasing life expectancy. Increasing understanding of AD pathogenesis suggests heterogeneous nature of this disease, with number of underlying mechanisms operating simultaneously, contributing to the ultimate phenotype. Neuropathological hallmarks of AD include senile plaques and neurofibrillary tangles, neuronal atrophy and cortical neurodegeneration. There is currently no cure for AD and the available treatments can provide only a degree of symptomatic benefit to patients with mild-to-moderate AD. In this review, we focus on the current understanding of AD, available symptomatic treatments and potential disease modifying opportunities being pursued in the pharmaceutical industry as well as in academia


Aging neurodegenerative diseases dementia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akiyama, H., Barger, S., Barnum, S., et al. (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging, 21: 383–421.PubMedGoogle Scholar
  2. Bimonte-Nelson, H.A., Hunter, C.L., Nelson, M.E. and Granholm, A.C. (2003) Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav Brain Res., 139: 47–57.PubMedGoogle Scholar
  3. Bongers, G., Leurs, R., Robertson, J., Raber, J. (2004) Role of H3-receptor-mediated signaling in anxiety and cognition in wild-type and Apoe–/–mice. Neuropsychopharmacology, 29: 441–449.PubMedGoogle Scholar
  4. Bourin, M., Ripoll, N., Dailly, E. (2003) Nicotinic receptors and Alzheimer’s disease. Curr Med Res Opin., 19: 169–177.PubMedGoogle Scholar
  5. Butterfield, D.A., Drake, J., Pocernich, C., Castegna, A. (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med., 7: 548–554.PubMedGoogle Scholar
  6. Capsoni, S., Giannotta, S., Cattaneo, A. (2002) Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci., 21: 15–28.PubMedGoogle Scholar
  7. Carson, J.A. and Turner, A.J. (2002) Beta-amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases? J Neurochem., 81: 1–8.PubMedGoogle Scholar
  8. Chauhan, V.P., Ray, I., Chauhan, A., Wisniewski, H.M. (1999) Binding of gelsolin, a secretory protein, to amyloid beta-protein. Biochem Biophys Res Commun., 258: 241–246.PubMedGoogle Scholar
  9. Cherny, R.A., Atwood, C.S., Xilinas, M.E., et al. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron, 30: 665–676.PubMedGoogle Scholar
  10. Choo-Smith, L.P. and Surewicz, W.K. (1997) The interaction between Alzheimer amyloid beta(1-40) peptide and ganglioside GM1-containing membranes. FEBS Lett., 402: 95–98.PubMedGoogle Scholar
  11. Courtney, C., Farrell, D., Gray, R., et al. (2004) Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet, 363: 2105–2115.PubMedGoogle Scholar
  12. Courtney, C., Farrell, D., Gray, R., et al. (2004) Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trail. Lancet, 363: 2105–2115.PubMedGoogle Scholar
  13. Crisby, M., Carlson, L.A. and Winblad, B. (2002) Statins in the prevention and treatment of Alzheimer disease. Alzheimer Dis Assoc Disord., 16: 131–136.PubMedGoogle Scholar
  14. Deane, R., Yan, S.D., Submamaryan, R.K., et al. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med., 9: 907–913.PubMedGoogle Scholar
  15. De Strooper, B. (2003) Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron, 38: 9–12.PubMedGoogle Scholar
  16. Dickson, D.W. (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurology, 56: 321–339.Google Scholar
  17. Distl, R., Meske, V., Ohm, T.G. (2001) Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol (Berl)., 101: 547–554.Google Scholar
  18. Dovey, H.F., John, V., Anderson, J.P., et al. (2001) Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem., 76: 173–181.PubMedGoogle Scholar
  19. Edbauer, D., Winkler, E., Regula, J.T., et al. (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol., 5: 486–488.PubMedGoogle Scholar
  20. Egan, M.F., Kojima, M., Callicott, J.H., et al. (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112: 257–269.PubMedGoogle Scholar
  21. Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., et al. (2002) Dietary intake of antioxidants and risk of Alzheimer disease. JAMA., 287: 3223–3229.PubMedGoogle Scholar
  22. Eriksdotter Jonhagen, M., Nordberg, A., Amberla, K., et al. (1998) Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement Geriatr Cogn Disord., 9: 246–257.PubMedGoogle Scholar
  23. Eriksen, J.L., Sagi, S.A., Smith, T.E., et al. (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest., 112: 440–449.PubMedGoogle Scholar
  24. Ertekin-Taner, N., Allen, M., Fadale, D., et al. (2004) Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat., 23: 334–342.PubMedGoogle Scholar
  25. Farlow, M., Anand, R., Messina, Jr. J., et al. (2000) A 52-Week Study of the Efficacy of Rivastigmine in Patients with Mild to Moderately Severe Alzheimer’s Disease. European Neurology, 44: 236–241.PubMedGoogle Scholar
  26. Farris, W., Mansourian, S., Leissring, M.A., et al. (2004) Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol., 164: 1425–1434.PubMedGoogle Scholar
  27. Fassbender, K., Simons, M., Bergmann, C., et al. (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. PNAS USA., 98: 5856–5861.PubMedGoogle Scholar
  28. Ferri, C.P., Prince, M., Brayne, C., et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet, 366: 2112–2117.PubMedGoogle Scholar
  29. Fillit, H., Weinreb, H., Cholst, I., et al. (1986) Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type. Psycho-neuroendocrinology, 11: 337–345.Google Scholar
  30. Fox, N.C., Black, R.S., Gilman, S., et al. (2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology, 64: 1563–1572.PubMedGoogle Scholar
  31. Frears, E.R., Stephens, D.J., Walters, C.E., et al. (1999) The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport, 10: 1699–1705.PubMedGoogle Scholar
  32. Friedhoff, L.T., Cullen, E.I., Geoghagen, N.S. and Buxbaum, J.D. (2001). Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol., 4: 127–130.PubMedGoogle Scholar
  33. Geldmacher, D.S., Provenzano, G., McRae, T., et al. (2003) Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease. Journal of the American Geriatrics Society 51: 937–944.PubMedGoogle Scholar
  34. Gilman, S., Koller, M., Black, R.S., et al. (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64: 1553–1562.PubMedGoogle Scholar
  35. Goedert, M. (1996) Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Ann, N. Y. Acad Sci., 777: 121–131.Google Scholar
  36. Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., et al. (1986) Abnormal phosphorylation of the microtubule associated protein t (tau) in Alzheimer cytoskeletoal pathology. PNAS USA., 83: 4913–4917.PubMedGoogle Scholar
  37. Grundman, M., Capparelli, E. and Kim, H.T. (2003) A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer’s disease patients. Life Sci., 73: 539–553.PubMedGoogle Scholar
  38. Hardy, J. (2003) Alzheimer’s disease: genetic evidence point to a single pathogenesis. Ann. Neurol., 54: 143–144.PubMedGoogle Scholar
  39. Hardy, J.A., Higgins, G.A. (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science., 256: 184–185.PubMedGoogle Scholar
  40. Hebert, L.E., Scherr, P.A., Bienias, J.L., et al. (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol., 60: 1119–1122.PubMedGoogle Scholar
  41. Ho, L., Qin, W., Pompl, P.N., et al. (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J., 18: 902–904.PubMedGoogle Scholar
  42. Hoglund, K., Wiklund, O., Vanderstichele, H., et al. (2004) Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol., 61: 333–337.PubMedGoogle Scholar
  43. Holmes, M., Maysinger, D., Foerster, A., et al. (2003) Neotrofin, a novel purine that induces NGF-dependent nociceptive nerve sprouting but not hyperalgesia in adult rat skin. Mol Cell Neurosci., 24: 568–580.PubMedGoogle Scholar
  44. Hong, L., Turner., R.T., Koelsch, G., et al. (2002) Crystal structure of memapsin 2 (b-secretase) in complex with an inhibitor OM00-3. Biochemistry, 41: 10963–10967.PubMedGoogle Scholar
  45. Hussain, I. (2004) The potential for BACE1 inhibitors in the treatment of Alzheimer’s disease. IDrugs, 7: 653–658.PubMedGoogle Scholar
  46. Ibach, B., Haen, E. (2004) Acetylcholinesterase inhibition in Alzheimer’s Disease. Curr Pharm Des., 10: 231–251.PubMedGoogle Scholar
  47. in t’ Veld, B.A., Ruitenberg, A., Hofman, A., et al. (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med., 345: 1515–1521.PubMedGoogle Scholar
  48. Kawarabayashi, T., Younkin, L.H., Saido, T.C., et al. (2001) Age-dependent changes in brain , CSF and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci., 21: 372–381.PubMedGoogle Scholar
  49. Kawarabayashi, T., Shoji, M., Younkin, L.H., et al. (2004) Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci., 24: 3801–3809.PubMedGoogle Scholar
  50. Kopan, R. and Ilagan, M. (2004) γ-Secretase: proteosome of the membrane? Nature Reviews Molecular Cell Biology, 5: 499–504.PubMedGoogle Scholar
  51. Kukull, W.A. and Ganguli, M. (2000) Epidemiology of dementia: concepts and overview. Neurol Clin., 18: 923–950.PubMedGoogle Scholar
  52. Kumar, U. (2005) Alzheimer’s Disease: Current and Future treatments. In: Aging Interventions and Therapies (Ed.: Rattan, S.) Pages 329–354, World Scientific, Singapore.Google Scholar
  53. Lezoualc’h, F. and Robert, S.J. (2003) The serotonin 5-HT4 receptor and the amyloid precursor protein processing. Exp Gerontol., 38: 159–166.PubMedGoogle Scholar
  54. Maelicke, A. (2000) Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Dement Geriatr Cogn Disord., 11 Suppl 1: 11–18.Google Scholar
  55. Mandelkow, E.M., Mandelkow, E. (1998) Tau in Alzheimer’s disease. Trends Cell Biol., 8: 425–427.PubMedGoogle Scholar
  56. Marks, M.J., Stitzel, J.A. and Collins, A.C. (1987) Influence of kinetics of nicotine administration on tolerance development and receptor levels. Pharmacol Biochem Behav., 27: 505–512.PubMedGoogle Scholar
  57. Marr, R.A., Guan, H., Rockenstein, E., et al. (2004) Neprilysin regulates amyloid Beta peptide levels. J Mol Neurosci., 22: 5–11.PubMedGoogle Scholar
  58. Maubach, K. (2003) GABA(A) receptor subtype selective cognition enhancers. Curr Drug Targets CNS Neurol Disord., 2: 233–239.PubMedGoogle Scholar
  59. Mohs, R.C., Doody, R.S., Morris, J.C., et al. (2001) A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology, 57: 481–488.PubMedGoogle Scholar
  60. Moore, A.H., O’Banion, M.K. (2000) Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Adv Drug Deliv Rev., 54: 1627–1656.Google Scholar
  61. Morgan, D., Gitter, B.D. (2004) Evidence supporting a role for anti-Abeta antibodies in the treatment of Alzheimer’s disease. Neurobiol Aging., 25: 605–608.PubMedGoogle Scholar
  62. Mori, T., Paris, D., Town, T., et al. (2001) Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J Neuropathol Exp Neurol., 60: 778–785.PubMedGoogle Scholar
  63. Mudher, A., Lovestone, S. (2002) Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci., 25: 22–26.PubMedGoogle Scholar
  64. Nicoll, J.A., Wilkinson, D., Holmes, C., et al. (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med., 9: 448–452.PubMedGoogle Scholar
  65. Oddo, S., Caccamo, A., Kitazawa, M., et al. (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging., 24: 1063–1070.PubMedGoogle Scholar
  66. Ohno, M., Sametsky, E., Younkin, N., et al. (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron, 41: 27–33.PubMedGoogle Scholar
  67. Orgogozo, J.M., Gilman, S., Dartigues, J.F., et al. (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61: 46–54.PubMedGoogle Scholar
  68. Palmer, G.C. (2001) Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets, 2: 241–271.PubMedGoogle Scholar
  69. Pangalos, M.N., Jacobsen, S.J. and Reinhart, P.H. (2005) Disease modifying strategies for the treatment of Alzheimer’s disease targeted at modulating levels of the beta-amyloid peptide. Biochemical Society Transactions, 33: 553–558.PubMedGoogle Scholar
  70. Panisset, M., Gauthier, S., Moessler, H. and Windisch, M. (2002) Cerebrolysin in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm., 109: 1089–1104.PubMedGoogle Scholar
  71. Parsons, C.G., Danysz, W., Quack, G. (1999) Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology, 38: 735–767.PubMedGoogle Scholar
  72. Phiel, C.J., Wilson, C.A., Lee, V.M. and Klein, P.S. (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature, 423: 435–439.PubMedGoogle Scholar
  73. Phinney, A.L., Horne, P., Yang, J., et al. (2003) Mouse models of Alzheimer’s disease: the long and filamentous road. Neurol Res., 25: 590–600.PubMedGoogle Scholar
  74. Rapp, S.R., Espeland, M.A., Shumaker, S.A., et al. (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA., 289: 2663–2672.PubMedGoogle Scholar
  75. Raskind, M.A., Peskind, E.R., Wessel, T. and Yuan, W. (2000) Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology, 54: 2261–2268.PubMedGoogle Scholar
  76. Raskind, M.A., Peskind, E.R., Truyen, L., et al. (2004) The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Archives of neurology, 61: 252–256.PubMedGoogle Scholar
  77. Raskind, M.A., Peskind, E.R., Truyen, L.B., et al. (2004) The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol., 61: 252–256.PubMedGoogle Scholar
  78. Reavill, C. and Rogers, D.C. (2001) The therapeutic potential of 5-HT6 receptor antagonists. Curr Opin Investig Drugs., 2: 104–109.PubMedGoogle Scholar
  79. Regland, B., Lehmann, W., Abedini, I., et al. (2001) Treatment of Alzheimer’s disease with clioquinol. Dement Geriatr Cogn Disord., 12: 408–414.PubMedGoogle Scholar
  80. Reisberg, B., Doody, R., Stoffler, A., et al. (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med., 348: 1333–1341.PubMedGoogle Scholar
  81. Ritchie, C.W., Bush, A.I., Mackinnon, A., et al. (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol., 60: 1685–1691.PubMedGoogle Scholar
  82. Robinson, S.R., Bishop, G.M., Lee, H.G. and Munch, G. (2004) Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging, 25: 609–615.PubMedGoogle Scholar
  83. Rockwood, K., Mintzer, J., Truyen, L., et al. (2001) Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial. Journal of neurology, neurosurgery, and psychiatry, 71: 589–595.PubMedGoogle Scholar
  84. Rogers, J., Kirby, L.C., Hempelman, S.R., et al. (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology, 43: 1609–1611.PubMedGoogle Scholar
  85. Rogers, S.L., Farlow, M.R., Doody, R.S., et al. (1998a) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology. 50: 136–145.Google Scholar
  86. Rogers, S.L., Doody, R.S., Mohs, R.C., et al. (1998b) Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Archives of Internal Medicine, 158: 1021–1031.Google Scholar
  87. Rogers, S.L., Doody, R.S., Pratt, R.D., et al. (2000) Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label Study. European neuropsychopharmacology, 10: 195–203.PubMedGoogle Scholar
  88. Sakaguchi, T., Yan, S.F., Yan, S.D., et al. (2003) Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest., 111: 959–972.PubMedGoogle Scholar
  89. Sano, M., Wilcock, G.K., van Baelen, B., et al. (2003) The effects of galantamine treatment on caregiver time in Alzheimer’s disease. International Journal of Geriatric Psychiatry, 18: 942–950.PubMedGoogle Scholar
  90. Schneider, L.S. and Tariot, P.N. (2003) Cognitive enhancers and treatments for Alzheimer’s disease. In Tasman, A., Kay, J. and Lieberman, J.A. (eds.) Psychiatry, 2nd edition John Wiley and Sons, London.Google Scholar
  91. Scott, J.A., Da Camara, C.C. and Early, J.E. (1999) Raloxifene: a selective estrogen receptor modulator. Am Fam Physician, 60: 1131–1139.PubMedGoogle Scholar
  92. Shie, F.S., Jin, L.W., Cook, D.G., et al. (2002) Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Neuroreport, 13: 455–459.PubMedGoogle Scholar
  93. Siemers, E., Skinner, M., Dean, R.A., et al. (2005) Safety, Tolerability, and Changes in Amyloid beta Concentrations After Administration of a gamma-Secretase Inhibitor in Volunteers. Clinical Neuropharmacology, 28: 126–132.PubMedGoogle Scholar
  94. Simons, M., Keller, P., Dichgans, J. and Schulz, J.B. (2001) Cholesterol and Alzheimer’s disease: is there a link? Neurology, 57: 1089–1093.PubMedGoogle Scholar
  95. Solomon, P.R., Adams, F., Silver, A., et al. (2002) Ginkgo for memory enhancement: a randomized controlled trial. JAMA., 288: 835–840.PubMedGoogle Scholar
  96. Soto, C., Saborio, G.P., Permanne, B. (2000) Inhibiting the conversion of soluble amyloid-beta peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer’s disease therapy. Acta Neurol Scand Suppl., 176: 90–95.PubMedGoogle Scholar
  97. Sparks, D.L., Sabbagh, M.N., Connor, D.J., et al. (2005) Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD. Current Alzheimer Research, 2: 343–353.PubMedGoogle Scholar
  98. Tanzi, R.E. and Bertram, L. (2001) New frontiers in Alzheimer’s disease genetics. Neuron, 32: 181–184.PubMedGoogle Scholar
  99. Tariot, P.N., Solomon, P.R., Morris, J.C., et al. (2000) A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology, 54: 2269–2276.PubMedGoogle Scholar
  100. Tariot, P.N., Loy, R., Ryan, J.M., et al. (2002) Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev., 54: 1567–1577.PubMedGoogle Scholar
  101. Tariot, P.N., Farlow, M.R., Grossberg, G.T., et al. (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA., 291: 317–324.PubMedGoogle Scholar
  102. van Duijn, C.M. and Hofman, A. (1991) Relation between nicotine intake and Alzheimer’s disease. BMJ., 302: 1491–1494.PubMedGoogle Scholar
  103. Wilcock, G.K., Lilienfeld, S. and Gaens, E. (2000) Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ, 321: 1445–1449.PubMedGoogle Scholar
  104. Wilcock, G.K., Birks, J., Whitehead, A., Evans, S.J. (2002) The effect of selegiline in the treatment of people with Alzheimer’s disease: a meta-analysis of published trials. Int J Geriatr Psychiatry., 17: 175–183.PubMedGoogle Scholar
  105. Wilcock, G., Howe, I., Coles, H., et al. (2003) A long-term comparison of galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs & aging, 20: 777–789.Google Scholar
  106. Wilkinson, D.G., Passmore, A.P., Bullock, R., et al. (2002) A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. International journal of clinical practice, 56: 441–446.PubMedGoogle Scholar
  107. Wimo, A., Winblad, B., Shah, S.N., et al. (2004) Impact of donepezil treatment for Alzheimer’s disease on caregiver time. Current medical research and opinion, 20: 1221–1225.PubMedGoogle Scholar
  108. Winblad, B., Engedal, K., Soininen, H., et al. (2001) A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology, 57: 489–495.PubMedGoogle Scholar
  109. Yamada, K., Nitta, A., Hasegawa, T., et al. (1997) Orally active NGF synthesis stimulators: potential therapeutic agents in Alzheimer’s disease. Behav Brain Res., 83: 117–122.PubMedGoogle Scholar
  110. Yan, S.D., Chen, X., Fu, J., et al. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature, 382: 685–691.PubMedGoogle Scholar
  111. Zhou, Y., Su, Y., Li, B., et al. (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science, 302: 1215–1217.PubMedGoogle Scholar
  112. Zlokovic, B.V. (2004) Clearing amyloid through the blood-brain barrier. J Neurochem., 89: 807–811.PubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Umesh Kumar
    • 1
  • Alexander Roland
    • 1
  • Stephen A. Burbidge
    • 1
  1. 1.Neurology and GI Centre of Excellence for Drug DiscoveryGlaxoSmithKlineNew Frontiers Science ParkEssex CM19 5AWUnited Kingdom

Personalised recommendations