Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 2 , Pages 118-125 , April 2006

Do cholinergic therapies have disease-modifying effects in Alzheimer’s disease?

  • Marwan N. Sabbagh

      Affiliations

    • Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA
    • Corresponding Author InformationCorresponding author. Tel.:623-875-6500; Fax: 623-875-6504.
    • ,
  • Martin R. Farlow

      Affiliations

    • Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
    • ,
  • Normal Relkin

      Affiliations

    • Department of Neurology, Weill Cornell Medical School, New York, NY, USA
    • ,
  • Thomas G. Beach

      Affiliations

    • Civin Laboratory for Neuropathology, Sun Health Research Institute, Sun City, AZ, USA

References 

  1. Perry EK , Johnson M , Kerwin JM , et al.   Convergent cholinergic activities in aging and Alzheimer’s disease . Neurobiol Aging . 1992;13:393–400
  2. Katzman R , Terry R , DeTeresa R , et al.   Clinical, pathological, and neurochemical changes in dementia (a subgroup with preserved mental status and numerous neocortical plaques) . Ann Neurol . 1988;23:138–144
  3. Beach TG , Honer WG , Hughes LH . Cholinergic fibre loss associated with diffuse plaques in the non- demented elderly (the preclinical stage of Alzheimer’s disease?) . Acta Neuropathol (Berl) . 1997;93:146–153
  4. Beach TG , Potter PE , Kuo YM , et al.   Cholinergic deafferentation of the rabbit cortex (a new animal model of Abeta deposition) . Neurosci Lett . 2000;283:9–12
  5. Potter P , Pandya Y , et al.   Cortical cholinergic deficit is associated with plaque development at preclinical stages of Alzheimer’s disease . Neurobiol Aging . 2004;25(S2):79
  6. Funato H , Yoshimura M , Kusui K , et al.   Quantitation of amyloid beta-protein (A beta) in the cortex during aging and in Alzheimer’s disease . Am. J. Pathol . 1998;152:1633–1640
  7. Davies L , Wolska B , Hilbich C , et al.   A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease (prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques) . Neurology . 1988;38:1688–1693
  8. Inestrosa NC , Alvarez A , Perez CA , et al.   Acetycholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils (possible role of the peripheral site of the enzyme) . Neuron . 1996;16(4):881–891
  9. Davis KL , Mohs RC , Marin D , et al.   Cholinergic markers in elderly patients with early signs of Alzheimer disease . JAMA . 1999;281:1401–1406
  10. DeKosky ST , Ikonomovic MD , Styren SD , et al.   Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment . Ann Neurol . 2002;51:145–155
  11. Wallace WC , Bragin V , Robakis NK , et al.   Increased biosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis of Meynert . Brain Res Mol Brain Res . 1991;10:173–178
  12. Wallace W , Ahlers ST , Gotlib J , et al.   Amyloid precursor protein in the cerebral cortex is rapidly and persistently induced by loss of subcortical innervation . Proc Natl Acad Sci U S A . 1993;90:8712–8716
  13. Rossner S , Schliebs R , Hartig W , Bigl V . 192IGG-saporin-induced selective lesion of cholinergic basal forebrain system (neurochemical effects on cholinergic neurotransmission in rat cerebral cortex and hippocampus) . Brain Res Bull . 1995;39:371–381
  14. Lin L , LeBlanc CJ , Deacon TW , Isacson O . Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system . Neuroreport . 1998;9:547–552
  15. Beach TG , Walker D , Sue L , et al.   Immunotoxin lesion of the cholinergic nucleus basalis causes Ab deposition (towards a physiologic animal model of Alzheimer’s disease) . Curr Med Chem . 2003;3:57–75
  16. Roher AE , Kuo YM , Potter PE , et al.   Cortical cholinergic denervation elicits vascular A beta deposition . Ann NY Acad Sci . 2000;903:366–373
  17. Beach TG , Walker DG , Roher AE , Potter PE . Anti-Amyloidogenic activity of cholinergic agents . Drug Dev Res . 2002;56:242–247
  18. Beach TG . Muscarinic agonists as preventative therapy for Alzheimer’s disease . Curr Opin Investig Drugs . 2002;3:1633–1636
  19. Farias GG , Godoy JA , Hernandez F , Avila J , Fisher A , Inestrosa NC . M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity (a role for Wnt signaling pathway) . Neurobiol Dis . 2004;17:337–348
  20. Holschneider DP , Waite JJ , Li MG , Scremin OU . Decreased cortical blood flow after intraventricular administration of the 192 IgG-saporin immunotoxin . Soc Neurosci Abs . 1997;23:1575
  21. Buxbaum JD , Oishi M , Chen HI , et al.   Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor . Proc Natl Acad Sci U S A . 1992;89:10075–10078
  22. NitschRM  , SlackBE  , WurtmanRJ  , GrowdonJH  . Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors . Science . 1992;28:304–307
  23. Hung AY , Haass C , Nitsch RM , et al.   Activation of protein kinase C inhibits cellular production of the amyloid beta-protein . J Biol Chem . 1993;268:22959–22962
  24. Bymaster FP , Wong DT , Mitch CH , et al.   Neurochemical effects of the M1 muscarinic agonist xanomeline (LY246708/NNC11-0232) . J Pharmacol Exp Ther . 1994;269:282–289
  25. Nitsch RM , Growdon JH . Role of neurotransmission in the regulation of amyloid beta-protein precursor processing . Biochem Pharmacol . 1994;47:1275–1284
  26. Haring R , Gurwitz D , Barg J , et al.   Amyloid precursor protein secretion via muscarinic receptors (reduced desensitization using the M1-selective agonist AF102B) . Biochem Biophys Res Commun . 1994;203:652–658
  27. Haring R , Gurwitz D , Barg J , et al.   NGF promotes amyloid precursor protein secretion via muscarinic receptor activation . Biochem Biophys Res Commun . 1995;213:15–23
  28. Eckols K , Bymaster FP , Mitch CH , Shannon HE , Ward JS , DeLapp NW . The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from Chinese hamster ovary-m1 cells . Life Sci . 1995;57:1183–1190
  29. Wolf BA , Wertkin AM , Jolly YC , et al.   Muscarinic regulation of Alzheimer’s disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells . J Biol Chem . 1995;270:4916–4922
  30. Muller DM , Mendla K , Farber SA , Nitsch RM . Muscarinic M1 receptor agonists increase the secretion of the amyloid precursor protein ectodomain . Life Sci . 1997;60:985–991
  31. Bymaster FP , Carter PA , Peters SC , et al.   Compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects . Brain Res . 1998;795:179–190
  32. DeLapp N , Wu S , Belagaje R , et al.   Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells . Biochem Biophys Res Commun . 1998;244:156–160
  33. Fisher A . Therapeutic strategies in Alzheimer’s disease (M1 muscarinic agonists) . Jpn J Pharmacol . 2000;84:101–112
  34. Hock C , Golombowski S , Muller-Spahn F , et al.   Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer’s disease and major depression - inverse correlation with dementia severity . Eur Neurol . 1998;39:111–118
  35. Muller D , Wiegmann H , Langer U , Moltzen-Lenz S , Nitsch RM . Lu 25-109, a combined m1 agonist and m2 antagonist, modulates regulated processing of the amyloid precursor protein of Alzheimer’s disease . J Neural Transm . 1998;105:1029–1043
  36. Savage MJ , Trusko SP , Howland DS , et al.   Turnover of amyloid beta-protein in mouse brain and acute reduction of its level by phorbol ester . J Neurosci . 1998;18:1743–1752
  37. Buxbaum JD , Koo EH , Greengard P . Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide . Proc Natl Acad Sci U S A . 1993;90:9195–9198
  38. Slack B , Nitsch R , Livneh E , et al.   Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha . J Bio Chem . 1993;268:21097–21101
  39. Greig NH , Sambamurti K , Yu QS , Brossi A , Bruinsma GB , Lahiri DK . An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease . Curr Alzheimer Res . 2005;2:281–290
  40. Shaw KT , Utsuki T , Rogers J , Yu QS , Sambamurti K , Brossi A , et al.   Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development . Proc Natl Acad Sci U S A . 2001;98(13):7605–7610
  41. Lahiri DK , Farlow MR . Differential effect of tacrine and physostigmine on the secretion of the beta-amyloid precursor protein in cell lines . Mol Neurosci . 1996;7(1):41–49
  42. Farber SA , Nitsch RM , Schulz JG , Wurtman RJ . Regulated secretion of beta-amyloid precursor protein in rat brain . J Neurosci . 1995;15:7442–7451
  43. Mori F , Lai CC , Fusi F , Giacobini E . Cholinesterase inhibitors increase secretion of APPs in rat brain cortex . Neuroreport . 1995;6:633–636
  44. Chong YH , Suh YH . Amyloidogenic processing of Alzheimer’s amyloid precursor protein in vitro and its modulation by metal ions and tacrine . Life Sci . 1996;59(7):545–547
  45. Racchi M , Sironi M , Caprera A , Konig G , Govoni S . Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein . Mol Psychiatry . 2001;6(5):520–528
  46. Pittel Z , Heldman E , Barg J , Haring R , Fisher A . Muscarinic control of amyloid precursor protein secretion in rat cerebral cortex and cerebellum . Brain Res . 1996;742:299–304
  47. Haroutunian V , Greig N , Pei XF , et al.   Pharmacological modulation of Alzheimer’s beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions . Brain Res Mol Brain Res . 1997;46:161–168
  48. Beach TG , KuoY  , Schwab C , Walker DG , Roher AE . Reduction of cortical amyloid beta levels in guinea pig brain after systemic administration of physostigmine . ?? Neurosci Lett . 2001;310:21–24
  49. Beach TG , Walker DG , Potter PE , Sue LI , Fisher A . Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists . Brain Res . 2001;905:220–223
  50. Nitsch RM , Deng M , Tennis M , Schoenfeld D , Growdon JH . The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease . Ann Neurol . 2000;48:913–918
  51. Hock C , Maddalena A , Raschig A , 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
  52. Basun H , Nilsberth C , Eckman C , Lannfelt L , Younkin S . Plasma levels of Abeta42 and Abeta40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine . Dement Geriatr Cogn Disord . 2002;14:156–160
  53. Lahiri DK , Farlow MR , Sambamurti K . The secretion of amyloid beta-peptide is inhibited the tacrine-treated human neuroblastoma cells . Brain Res Mol Brain Res . 1998;2(2):131–140
  54. Zimmerman M , Gardoni G , Marcello E , Colciaghi E , et al.   Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines . J Neurochem . 2004;90(6):1489–1499
  55. Boronni B , Colchiaghi F , Pastorino L , Pettenati C , et al.   Amyloid precursor protein in platelets of patients with Alzheimer’s disease (effect of acetycholinesterase inhibitor treatment) . Arch Neurol . 2001;58(3):442–446
  56. Borroni B , Colchiaghi F , Pastorino L , Archetti S , et al.   ApoE genotype influences the biological effect at donepezil on APP metabolism in Alzheimer disease (evidence from a peripheral model) . Eur Neuropsychopharmacol . 2002;12(3):195–200
  57. Liu HC , Chi CW , Ko SY , Want HC , et al.   Cholinesterase inhibitor affects the amyloid precursor protein isoforms in patients with Alzheimer’s disease . Dementia Geriatr Cogn Disord . 2005;19(5-6):345–348
  58. Hellstrom-Lindahl E , Court J , Keverne J , et al.   Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice . Eur J Neurosci . 2004;19:2703–2710
  59. Nordberg A , Hellstrom-Lindahl E , Lee M , et al.   Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer’s disease (APPsw) . J Neurochem . 2002;81:655–658
  60. Arias E , Gallego-Sandin S , Villaroya M , Garcia AG , Lopez MG . Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells (roll of nicotinic receptors) . J Pharmacol Exp Ther . 2005;315(3):1346–1353
  61. Arias E , Ales E , Gabilan NH , Cano-Abad MD , Villaroya M , Garcia AG , et al.   Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin (involvement of nicotinic acetylcholine receptors) . Neuropharmacology . 2004;46(1):103–114
  62. Kihara T , Sawada H , Nakmizo T , Kanki R , Yamashita H , Maelicke A , et al.   Galantamine modulate nicotinic receptor and blocks Abeta-enhanced glutamate toxicity . Biochem Biophys Res Commun . 2004;325(3):976–982
  63. Bullock R , Dengiz A . Cognitive performance in patients with Alzheimer’s disease receiving cholinesterase inhibitors for up to 5 years . Int J Clin Pract . 2005;59(7):817–822
  64. Stern RG , Mohs RC , Davidson M , et al.   A longitudinal study of Alzheimer’s disease (measurement, rate, and predictors of cognitive deterioration) . Am J Psychiatry . 1994;151(3):390–396
  65. Doraiswamy PM , Kaiser L , Bieber F , Garman RL . The Alzheimer’s Disease Assessment Scale (evaluation of psychometric properties and patterns of cognitive decline in multicenter clinical trials of mild to moderate Alzheimer’s disease) . Alzheimer Dis Assoc Disord . 2001;15(4):174–183
  66. Doody RS , Dunn JK , Clark CM , et al.   Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer’s disease . Dement Geriatr Cogn Disord . 2001;12(4):295–300
  67. Winblad B , Engedal K , Soininen H , et al.   A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD . Neurology . 2001;57(3):489–495
  68. Matthews HP , Korbey J , Wilkinson DG , Rowden J . Donepezil in Alzheimer’s disease (eighteen months from Southampton Memory Clinic) . Int J Geriatric Psychiatry . 2000;15:713–720
  69. Rogers SL , Friedhoff LT . Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease (interim analysis of the results of a US multicentre open label extension study) . Eur Neuropsychopharmacol . 1998;8:67–75
  70. Doody R , Geldmacher D , Gordon B , et al.   Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease . Arch Neurol . 2001;58:427–433
  71. 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 extension study) . Eur Neuropsychopharmacol . 2000;10:195–203
  72. Farlow M , Potkin S , Koumaras B , Veach J , Mirski D . Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week, Alzheimer disease trial . Arch Neurol . 2003;60(6):843–848
  73. Leber P . Observations and suggestions on antidementia drug development . Alzheimer Dis Assoc Disord . 1996;10(suppl1):31–35
  74. Small GW , Kaufer D , Mendiondo MS , Quarg P , Spiegel R . Cognitive performance in Alzheimer’s disease patients receiving rivastigmine for up to 5 years . Int J Clin Pract . 2005;59(4):473–477
  75. Rainer M , Mucke HAM . Int J Geriatr Psychopharmacol . 1998;1:197–201
  76. Grossberg C , Irwin P , Satlin A , Mesenbrink P , Spiegel R . Rivastigmine in Alzheimer disease (efficacy over two years) . Am J Geriatr Psychiatry . 2004;12(4):420–431
  77. Small GW , Kaufer D , Quarg P , Spiegel R . Poster presented at the 9th ICADRD . Neurobiol Aging . 2004;25(S2):79
  78. Tariot PN , Kershaw P . Galantamine demonstrates cognitive benefits in patients with AD for at least 18 months . Neurology . 2002;58:A277–A278
  79. Pirttila T , Wilcock G , Truyen L , Damaraju CV . Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease (multicenter trial) . Eur J Neurol . 2004;11(11):734–741
  80. Raskind MA , Peskind ER , Truyen L , Kershaw P , Damaraju CV . The cognitive benefits of galantamine are sustained for at least 36 months . Arch Neurol . 2004;61:252–256
  81. Farlow MR , Lilly ML  ENA 713 B352 Study Group . Rivastigmine (an open-label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years) . BMC Geriatrics . 2005;5(1):3
  82. Thal LJ , Carta A , Clarke WR , Ferris SH , et al.   A 1-year multicenter, placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer’s disease . Neurology . 1996;47(3):705–711
  83. Thal LJ , Calvani M , Amato A , Carta A . A 1-year controlled trial of acetyl-l-carnitine in early-onset AD . Neurology . 2000;55(6):805–810
  84. Aisen PS , Davis KL , Berg JD , Schafer K , et al.   A randomized controlled trial of prednisone in Alzheimer’s disease. Alzheimer’s Disease Cooperative Study . Neurology . 2000;54(3):588–593
  85. Aisen PS , Schafer KA , Grundman M , Pfeiffer E , et al.   Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression (a randomized controlled trial) . JAMA . 2003;289(21):2819–2826
  86. Reines SA , Block GA , Morris JC , et al.   Rofecoxib (no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study) . Neurology . 2004;62(1):66–71
  87. Gilman S , Koller M , Black RS , Jenkins L , et al.   Clinical effects of Abeta immunization (AN1792) . 2005;64(9):1553–1562
  88. Petersen RC , Thomas RG , Grundman M , et al.  Alzheimer’s Disease Cooperative Study Group   Vitamin E and donepezil for the treatment of mild cognitive impairment . N Engl J Med . 2005;352(23):2379–2388 Epub 2005 Apr 13
  89. Courtney C , Farrell D , Gray R , Hills R , et al.   Long-term donepezil treatment in 565 patients with Alzheimer’s disease AD 2000 (randomised double-blind trial) . Lancet . 2004;363(9427):2105–2115
  90. Krishnan KRR , Charles HC , Doraiswamy PM , 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
  91. Hashimoto M , Kazui H , Matsumoto K , Nakano Y , Yasuda M , Mori E . Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? . Am J Psychiatry . 2005;162(4):676–682
  92. Tune LE , Hoffman JM , Tisco PJ , et al.   Donepezil HCL maintains global glucose activity in patients with Alzheimer’s disease; results of a 24 weeks study . J Cereb Blood Flow Metab . 1999;19(suppl 1):5838
  93. Potkin SG , Anand R , Fleming K , Alva G , et al.   Brain metabolic and clinical effects of rivastigmine in Alzheimer’s disease . Int J Neuropsychopharmacol . 2001;4(3):223–230
  94. Stefanova E , Wall A , Almkvist O , et al.   Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer’s disease . J Neural Transmission . 2005; July 29[epub ahead of print].
  95. Mega MS , Dinov ID , Porter V , Chow G , et al.   Metabolic patterns associated with the clinical response to galantamine therapy (a fluorodeoxyglucose f18 positron emission tomographic study) . Arch Neurol . 2005;62(5):721–728
  96. Knopman D , Schneider L , Davis K , et al.   Long-term tacrine (Cognex) treatment (effects on nursing home placement and mortality, Tactrine Study Group) . Neurology . 1996;47(1):166–177
  97. Geldmacher D , Provenzanok G , McRae T , et al.   Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease . J Am Ger Soc . 2003;51:937–944
  98. Lopez OL , Becker JT , Saxton J , Sweet RA , Klunk W , DeKosky ST . Alteration of a clinically meaningful outcome in the natural history of Alzheimer’s disease by cholinesterase inhibition . 2005;53(1):83–87

PII: S1552-5260(06)00041-0

doi: 10.1016/j.jalz.2006.02.001

Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 2 , Pages 118-125 , April 2006

Article Tools