Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 4, Issue 2 , Pages 65-79 , March 2008

Disease-modifying therapies in Alzheimer’s disease⁎

  • Stephen Salloway

      Affiliations

    • Department of Clinical Neuroscience, Division of Biology and Medicine, Brown Medical School, Providence, RI, USA
    • ,
  • Jacobo Mintzer

      Affiliations

    • Division of Translational Research, Neurosciences Department, Medical University of South Carolina Alzheimer’s Research and Clinical Programs, Charleston, SC, USA
    • ,
  • Myron F. Weiner

      Affiliations

    • Department of Psychiatry and Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
    • ,
  • Jeffrey L. Cummings

      Affiliations

    • Departments of Neurology, Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    • Corresponding Author InformationCorresponding author. Tel.: 310-794-3665; fax: 310-206-5287.

References 

  1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119–1122
  2. Ernst RL, Hay JW. The US economic and social costs of Alzheimer’s disease revisited. Am J Public Health. 1994;84:1261–1264
  3. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356
  4. Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004;63:1624–1628
  5. McLean C, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol. 1999;46:860–866
  6. Selkoe DJ. Presenilins, beta-amyloid precursor protein and the molecular basis of Alzheimer’s disease. Clin Neurosci Res. 2001;1:91–103
  7. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–357
  8. Cummings JL. Drug therapy: Alzheimer’s disease. N Engl J Med. 2004;351:56–67
  9. Roher AE, Weiss N, Kokjohn TA, Kuo YM, Kalback W, Anthony J, et al. Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease. Biochemistry. 2002;41:11080–11090
  10. Cummings JL. Challenges to demonstrating disease-modifying effects in Alzheimer’s disease clinical trial. Alzheimer’s & Dementia. 2006;2:263–271
  11. Bay E. Aphasia and nonverbal disorders of language. Brain. 1962;85:411
  12. Mani RB. The evaluation of disease modifying therapies in Alzheimer’s disease: a regulatory viewpoint. Stat Med. 2004;23:305–314
  13. 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
  14. Sampaio C. Alzheimer disease: disease modifying trials; where are we? where do we need to go? a reflective paper. J Nutr Health Aging. 2006;10:113–115
  15. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–177
  16. Lavie V, Becker M, Cohen-Kupiec R, Yacoby I, Koppel R, Wedenig M, et al. EFRH-phage immunization of Alzheimer’s disease animal model improves behavioral performance in Morris water maze trials. J Mol Neurosci. 2004;24:105–113
  17. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54
  18. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron. 2003;38:547–554
  19. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–1562
  20. Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005;64:1563–1572
  21. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–452
  22. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol. 2004;14:11–20
  23. Albert ML, Reches A, Silverberg R. Associative visual agnosia without alexia. Neurology. 1975;25:322
  24. Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75:1472–1474
  25. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 2001;4:231–232
  26. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet. 2001;10:1317–1324
  27. Asai M, Hattori C, Iwata N, Saido TC, Sasagawa N, Szabó B, et al. The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice. J Neurochem. 2006;96:533–540
  28. Jacobsen JS, Reinhart P, Pangalos MN. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer’s disease. NeuroRx. 2005;2:612–626
  29. Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, et al. The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther. 2003;305:864–871
  30. El Mouedden M, Vandermeeren M, Meert T, Mercken M. Reduction of Abeta levels in the Sprague Dawley rat after oral administration of the functional gamma-secretase inhibitor, DAPT: a novel non-transgenic model for Abeta production inhibitors. Curr Pharm Des. 2006;12:671–676
  31. May PC, Yang Z, Li W, Hyslop PA, Siemers E, Boggs LN, et al. Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 dihydrate in PDAPP transgenic mice and non-transgenic mice. Neurobiol Aging. 2004;25(Suppl 25):S65
  32. Barten DM, Guss VL, Cosa JA, Loo A, Hansel SB, Zheng M, et al. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther. 2005;312:635–643
  33. Comery TA, Marton RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, et al. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci. 2005;25:8898–8902
  34. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 2006;66:602–604
  35. Micchelli CA, Esler WP, Kimberly WT, Jack C, Berezovska O, Kornilova A, et al. Gamma-secretase/presenilin inhibitors for Alzheimer’s disease phenocopy Notch mutations in Drosophila. Faseb J. 2003;17:79–81
  36. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 2001;294:2155–2158
  37. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–12882
  38. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996;47:425–432
  39. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer’s disease progression: a randomized controlled trial. JAMA. 2003;289:2819–2826
  40. Morihara T, Chu T, Ubeda O, Beech W, Cole GM. Selective inhibition of Abeta42 production by NSAID R-enantiomers. J Neurochem. 2002;83:1009–1012
  41. O’Donnell BF, Drachman DA, Barnes HJ, Peterson KE, Swearer JM, Lew RA. Incontinence and troublesome behaviors predict institutionalization in dementia. J Geriatr Psychiatry Neurol. 1992;5:45–52
  42. Mintzer JE, Wilcock GK, Black SE, Zavitz KH, Hendrix SB. MPC-7869, a selective Abeta42-lowering agent, delays time to clinically significant psychiatric adverse events in Alzheimer’s disease (analysis from a 12-month phase 2 trial). Presented as a poster exhibit at the 10th International Conference on Alzheimer’s Disease and Related Disorders, Madrid, Spain. 2006;
  43. Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28:537–547
  44. Aisen P, Gauthier S, Vellas B, Briand R, Saumier D, Laurin J, et al. Tramiprosate (Alzhemed™): A potential treatment for Alzheimer’s disease. In: 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, Geneva, Switzerland. 2006;
  45. Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P, et al. A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology. 2006;67:1757–1763
  46. Townsend M, Cleary JP, Mehta T, Hofmeister J, Lesne S, O’Hare E, et al. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Ann Neurol. 2006;60:668–676
  47. Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, et al. Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:18787–18792
  48. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439–1443
  49. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault , et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59:223–227
  50. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta42 and Abeta40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001;98:5856–5861
  51. Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002;52:346–350
  52. Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005;62:753–757
  53. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630
  54. Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, et al. Do statins reduce risk of incident dementia and Alzheimer disease? (the Cache County Study). Arch Gen Psychiatry. 2005;62:217–224
  55. Craft S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005;26(Suppl 1):65–69
  56. Pedersen WA, Flynn ER. Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis. 2004;17:500–506
  57. 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
  58. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana 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. 2005;13:950–958
  59. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J. 2006;6:246–254
  60. Geldmacher DS, Frolich L, Doody RS, Erkinjuntti T, Vellas B, Jones RW, et al. Realistic expectations for treatment success in Alzheimer’s disease. J Nutr Health Aging. 2006;10:417–429
  61. Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord. 2006;20:298–301
  62. Cuajungco MP, Frederickson CJ, Bush AI. Amyloid-beta metal interaction and metal chelation. Subcell Biochem. 2005;38:235–254
  63. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron. 2001;30:665–676
  64. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685–1691
  65. Dedeoglu A, Cormier K, Payton S, Tseitlin KA, Kremsky JN, Lai L, et al. Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer’s amyloidogenesis. Exp Gerontol. 2004;39:1641–1649
  66. Lee JY, Friedman JE, Angel I, Kozak A, Koh JY. The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice. Neurobiol Aging. 2004;25:1315–1321
  67. Reznichenko L, Amit T, Zheng H, Avramovich-Tirosh Y, Youdim MB, Weinreb O, et al. Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer’s disease. J Neurochem. 2006;97:527–536
  68. Fisher A, Pittel Z, Haring R, Bar-Ner N, Kliger-Spatz M, Natan N, et al. M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease: implications in future therapy. J Mol Neurosci. 2003;20:349–356
  69. Fisher A, Brandeis R, Bar-Ner RH, Kliger-Spatz M, Natan N, Sonego H, et al. AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer’s disease. J Mol Neurosci. 2002;19:145–153
  70. Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 2006;49:671–682
  71. Hock C, Maddalena A, Raschig A, Müller-Spahn F, Eschweiler G, Hager K, et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer’s disease. Amyloid. 2003;10:1–6
  72. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54:465–473
  73. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907–913
  74. Matsuoka Y, Saito M, LaFrancois J, Saito M, Gaynor K, Olm V, et al. Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci. 2003;23:29–33
  75. Park JH, Gimbel DA, GrandPre T, Lee JK, Kim JE, Li W, et al. Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci. 2006;26:1386–1395
  76. Park JH, Widi GA, Gimbel DA, Harel NY, Lee DH, Strittmatter SM. Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer’s transgenic mice. J Neurosci. 2006;26:13279–13286
  77. Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, et al. Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer’s disease. Faseb J. 2004;18:323–325
  78. Fillenbaum GG, Kuchibhatla MN, Hanlon JT, Artz MB, Pieper CF, Schmader KE, et al. Dementia and Alzheimer’s disease in community-dwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother. 2005;39:2009–2014
  79. Maxwell CJ, Hicks MS, Hogan DB, Basran J, Ebly EM. Supplemental use of antioxidant vitamins and subsequent risk of cognitive decline and dementia. Dement Geriatr Cogn Disord. 2005;20:45–51
  80. Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004;61:82–88
  81. Devanand DP, Jacobs DM, Tang MX, Del Castillo-Castaneda C, Sano M, Marder K, et al. The course of psychopathologic features in mild to moderate Alzheimer’s disease. Arch Gen Psychiatry. 1997;54:257–263
  82. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–2388
  83. Frank B, Gupta S. A review of antioxidants and Alzheimer’s disease. Ann Clin Psychiatry. 2005;17:269–286
  84. Cole GM, Yang F, Lim GP, Cummings J, Masterman D, Frautschy S. A rational for curcuminoids for the prevention or treatment of Alzheimer’s disease. Curr Med Chem. 2003;3:15–25
  85. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer’s disease. Curr Alzheimer Res. 2005;2:131–136
  86. Asano T, Mori T, Shimoda T, Shinagawa R, Satoh S, Yada N, et al. Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B. Curr Drug Targets CNS Neurol Disord. 2005;4:127–142
  87. Kato H, Kurosaki R, Oki C, Araki T. Arundic acid, an astrocyte-modulating agent, protects dopaminergic neurons against MPTP neurotoxicity in mice. Brain Res. 2004;1030:66–73
  88. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324:1149–1155
  89. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55:1449–1455
  90. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry. 1998;13:235–239
  91. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346:476–483
  92. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci. 2002;22:1752–1762
  93. Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006;107:591–593
  94. Finch CE, Longo V, Miyao A, Morgan TE, Rozovsky I, Soong Y, et al. Inflammation in Alzheimer’s disease. In:  Chesselet M-F editors. Molecular mechanisms of neurodegenerative diseases. Totowa, NJ: Human Press; 2001;p. 87–110
  95. Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, et al. A randomized controlled trial of prednisone in Alzheimer’s disease. Neurology. 2000;54:588–593
  96. Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology. 1999;53:197–201
  97. Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, et al. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004;62:66–71
  98. Aisen PS, Schmeidler J, Pasinetti GM. Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology. 2002;58:1050–1054
  99. Thal LJ, Ferris SH, Kirby L, Block GA, Lines GR, Yuen E, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005;30:1204–1215
  100. Harkany T, Abraham I, Timmerman W, Laskay G, Toth B, Sasvari M, et al. Beta-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci. 2000;12:2735–2745
  101. Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N. NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci U S A. 2006;103:2892–2897
  102. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology. 1999;38:735–767
  103. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003;348:1333–1341
  104. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317–324
  105. Wenk GL, Baker LM, Stoehr JD, Hauss-Wegrzyniak B, Danysz W. Neuroprotection by novel antagonists at the NMDA receptor channel and glycineB sites. Eur J Pharmacol. 1998;347:183–187
  106. Bannerman DM, Deacon RM, Brady S, Bruce A, Sprengel R, Seeburg PH, et al. A comparison of GluR-A-deficient and wild-type mice on a test battery assessing sensorimotor, affective, and cognitive behaviors. Behav Neurosci. 2004;118:643–647
  107. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J Neurosci. 1998;18:2740–2747
  108. Quirk JC, Nisenbaum ES. LY404187: a novel positive allosteric modulator of AMPA receptors. CNS Drug Rev. 2002;8:255–282
  109. Dicou E, Rangon CM, Guimiot F, Spedding M, Gressens P. Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain. Brain Res. 2003;970:221–225
  110. Buccafusco JJ, Weiser T, Winter K, Klinder K, Terry AV. The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys. Neuropharmacology. 2004;46:10–22
  111. Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA. Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol. 2005;3:e299
  112. Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:24–35
  113. Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH, Gallo JM, et al. Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol. 1994;4:1077–1086
  114. Lovestone S, Davis D, Webster MT, Kaech S, Brion JP, Matus A, et al. Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatry. 1999;45:995–1003
  115. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005;102:6990–6995
  116. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature. 2003;423:435–439
  117. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, et al Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2003;100:10032–10037
  118. Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, et al. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci. 2002;22:2035–2043
  119. Rohn TT, Head E, Nesse WH, Cotman CW, Cribbs DH. Activation of caspase-8 in the Alzheimer’s disease brain. Neurobiol Dis. 2001;8:1006–1016
  120. Gastard MC, Troncoso JC, Koliatsos VE. Caspase activation in the limbic cortex of subjects with early Alzheimer’s disease. Ann Neurol. 2003;54:393–398
  121. Kang HJ, Yoon WJ, Moon GJ, Kim DY, Sohn S, Kwon HJ, et al. Caspase-3-mediated cleavage of PHF-1 tau during apoptosis irrespective of excitotoxicity and oxidative stress: an implication to Alzheimer’s disease. Neurobiol Dis. 2005;18:450–458
  122. Abrahamson EE, Ikonomovic MD, Ciallella JR, Hope CE, Paljug WR, Isanski BA, et al. Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome. Exp Neurol. 2006;197:437–450
  123. Chen YH, Zhang YH, Zhang HJ, Liu DZ, Gu M, Li JY, et al. Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. J Med Chem. 2006;49:1613–1623
  124. Saura J, Luue JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994;62:15–30
  125. Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal LJ, Masliah E. Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer’s disease. J Neural Transm. 2003;110:789–801
  126. Youdim MB, Bar Am O, Yogev-Falach M, Weinrab O, Maruyama W, Naoi M, et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res. 2005;79:172–179
  127. Hellstrom-Lindahl E, Court J, Keverne J, Svedberg M, Lee M, Marutle A, et al. Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. Eur J Neurosci. 2004;19:2703–2710
  128. Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol. 2002;53:633–640
  129. Lenzken SC, Lanni C, Govoni S, Lucchelli A, Schettini G, Racchi M. Nicotinic component of galantamine in the regulation of amyloid precursor protein processing. Chem Biol Interact. 2007;165:138–145
  130. Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, et al. TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev. 2004;10:147–166
  131. Lopez OL, Becker JT, Wisniewski S, Saxton J, Kaufer DI, DeKosky ST. Cholinesterase inhibitor treatment alters the natural history of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2002;72:310–314
  132. Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease. Am J Psychiatry. 2003;160:2003–2011
  133. Francis PT, Nordberg A, Arnold SE. A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer’s disease?. Trends Pharmacol Sci. 2005;26:104–111
  134. Mori E, Hashimoto M, Krishnan KR, Doraiswamy PM. What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors?. Alzheimer Dis Assoc Disord. 2006;20:S19–S26
  135. Racchi M, Mazzucchelli M, Porrello E, Lanni C, Govoni S. Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacol Res. 2004;50:441–451
  136. Sabbagh MN, Farlow MR, Relkin N, Beach TG. Do cholinergic therapies have disease-modifying effects in Alzheimer’s disease?. Alzheimer’s & Dementia. 2006;2:118–125
  137. Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:S12–S18
  138. Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol. 2000;10:195–203
  139. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736
  140. Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001;24:1217–1281
  141. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006;110:167–173
  142. Williams LR, Varon S, Peterson GM, Wictorin K, Fischer W, Bjorklund A, et al. Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc Natl Acad Sci U S A. 1986;83:9231–9235
  143. Chen KS, Nishimura MC, Armanini MP, Crowley C, Spencer SD, Phillips HS. Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J Neurosci. 1997;17:7288–7296
  144. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11:551–555
  145. Ruether E, Husmann R, Kinzler E, Diabl E, Klingler D, Spatt J, et al. A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Int Clin Psychopharmacol. 2001;16:253–263
  146. Fournier J, Steinberg R, Gauthier T, Keane PE, Guzzi U, Coude FX, et al. Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates. Neuroscience. 1993;55:629–641
  147. Labie C, Lafon C, Marmouget C, Saubusse P, Fournier J, Keane PE, et al. Effect of the neuroprotective compound SR57746A on nerve growth factor synthesis in cultured astrocytes from neonatal rat cortex. Br J Pharmacol. 1999;127:139–144
  148. Duong FH, Warter JM, Poindron P, Passilly P. Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic survival of purified mouse motoneurons. Br J Pharmacol. 1999;128:1385–1392
  149. Fournier J, Keane PE, Ferrara P, Soubrie P. SR57746A: An orally active non-peptide compound with neurotrophic and neuroprotective effects. CNS Drug Reviews. 1997;3:148–167
  150. Lemaire L, Fournier J, Ponthus C, Le Fur Y, Confort-Gouny S, Vion-Dury J, et al. Magnetic resonance imaging of the neuroprotective effect of xaliproden in rats. Invest Radiol. 2002;37:321–327
  151. Rockenstein E, Adame A, Mante M, Moessler H, Windisch M, Masliah E. The neuroprotective effects of Cerebrolysin in a transgenic model of Alzheimer’s disease are associated with improved behavioral performance. J Neural Transm. 2003;110:1313–1327
  152. Panisset M, Gauthier S, Moessler H, Windisch M. Cerebrolysin in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm. 2002;109:1089–1104
  153. Alvarez XA, Cacabelos R, Laredo M, Couceiro V, Sampredo C, Varela M, et al. A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Eur J Neurol. 2006;13:43–54
  154. Smith DE, Roberts J, Gage FH, Tuszynski MH. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc Natl Acad Sci U S A. 1999;96:10893–10898
  155. Tuszynski MH, Roberts J, Senut MC, Gage FH. Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. U HS Gene Ther. 1996;3:305–314
  156. Gandy S, Martins RN, Buxbaum J. Molecular and cellular basis for anti-amyloid therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2003;17:259–266
  157. Citron M. Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:677–685
  158. Wolfe MS. Therapeutic strategies for Alzheimer’s disease. Nat Rev Drug Discov. 2002;1:859–866
  159. Saver JL, Kalafut M. Combination therapies and the theoretical limits of evidence-based medicine. Neuroepidemiology. 2001;20:57–64
  160. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathias C, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci. 2002;5:452–457
  161. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408:979–982
  162. Wilcock DM, Roiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, et al. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004;1:24
  163. Ferris SH, Aisen PS, Cummings J, Galasko D, Salmon DP, Schneider L, et al. ADCS Prevention Instrument Project: overview and initial results. Alzheimer Dis Assoc Disord. 2006;20(Suppl 3):S109–S123
  164. Jack CR, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology. 2003;60:253–260
  165. Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN. Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease. Arch Neurol. 2000;57:339–344
  166. Schott JM, Price SL, Frost C, Whitwell JL, Rossor MN, Fox NC. Measuring atrophy in Alzheimer disease: a serial MRI study over 6 and 12 months. Neurology. 2005;65:119–124
  167. DeCarli C, Frisoni GB, Clark CM, Harvey D, Grundman M, Petersen RC, et al. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol. 2007;64:108–115
  168. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–319
  169. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003;289:2094–2103
  170. Montine TJ, Beal MF, Cudkowicz ME, O’Donnell H, Margolin RA, McFarland L, et al. Increased CSF F2-isoprostane concentration in probable AD. Neurology. 1999;52:562–565
  171. Pratico D, Clark CM, Lee VM-Y, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol. 2000;48:809–812
  172. Yao Y, Clark CM, Trojanowski JQ, Lee VM-Y, Pratico D. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment. Ann Neurol. 2005;58:623–626

PII: S1552-5260(07)00632-2

doi: 10.1016/j.jalz.2007.10.001

Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 4, Issue 2 , Pages 65-79 , March 2008

Article Tools

* Image Usage & Resolution