title: Update on the pharmacological treatment of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Worldwide prevalence of the disease is estimated at more than 24 million cases. With aging of populations, this number will likely increase to more than 80 million cases by the year 2040. The annual incidence worldwide is estimated at 4.6 million cases which is the equivalent of one new case every seven seconds! The pathophysiology of AD is complex and largely misunderstood. It is thought to start with the accumulation of beta-amyloid (αβ) that leads to deposition of insoluble neuritic or senile plaques. Secondary events in this "amyloid cascade" include hyperphosphorylation of the protein tau into neurofibrillary tangles, inflammation, oxidation, and excitotoxicity that eventually cause activation of apoptotis, cell death and neurotransmitter deficits. This review will briefly summarize recent advances in the pathophysiology of AD and focus on the pharmacological treatment of the cognitive and functional symptoms of AD. It will discuss the roles of vascular prevention, cholinesterase inhibitors and an NMDA-antagonist in the management of AD. It will address the issues thought to be related to the lack of persistence or discontinuation of therapy with cholinesterase inhibitors shown in recent studies and some of the solutions proposed. These include setting realistic expectations in light of a neurodegenerative condition and available symptomatic treatments, slowly titrating medications, and using alternate routes of administration. Finally, it will introduce future therapeutic options currently under study.
authors.affiliation: Department of Medicine, University of Montreal, Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame, Service de Gériatrie, 1560 Sherbrooke Est, Montreal, Quebec, H2L 4M1. fadi.massoud.chum@ssss.gouv.qc.ca
authors.forename: Fadi
authors.initials: F
authors.lastname: Massoud
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
references.citation: Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S22-32
references.pmid: 9236949
references.citation: Expert Opin Drug Saf. 2009 Jan;8(1):89-109
references.pmid: 19236221
references.citation: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001747
references.pmid: 16437436
references.citation: J Neurol Neurosurg Psychiatry. 2004 May;75(5):677-85
references.pmid: 15090558
references.citation: Neurology. 2005 May 10;64(9):1553-62
references.pmid: 15883316
references.citation: J Clin Invest. 2004 May;113(10):1384-7
references.pmid: 15146234
references.citation: J Am Geriatr Soc. 2003 Jul;51(7):937-44
references.pmid: 12834513
references.citation: Int J Geriatr Psychiatry. 2009 May;24(5):479-88
references.pmid: 18985627
references.citation: Am J Hypertens. 1999 Nov;12(11 Pt 1):1130-4
references.pmid: 10604491
references.citation: J Neurosci. 1992 Feb;12(2):376-89
references.pmid: 1346802
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Lancet Neurol. 2008 Sep;7(9):805-11
references.pmid: 18667360
references.citation: N Engl J Med. 2004 Jul 1;351(1):56-67
references.pmid: 15229308
references.citation: Nat Rev Neurosci. 2003 Feb;4(2):131-8
references.pmid: 12563284
references.citation: Biochem Soc Symp. 2001;(67):81-8
references.pmid: 11447842
references.citation: BMJ. 2005 Aug 6;331(7512):321-7
references.pmid: 16081444
references.citation: Alzheimer Dis Assoc Disord. 2004 Apr-Jun;18 Suppl 1:S24-9
references.pmid: 15249845
references.citation: Trends Pharmacol Sci. 1996 Oct;17(10):348-55
references.pmid: 8979769
references.citation: J Neurol Neurosurg Psychiatry. 2002 Mar;72(3):310-4
references.pmid: 11861686
references.citation: Trends Neurosci. 2002 Jan;25(1):22-6
references.pmid: 11801334
references.citation: Expert Opin Pharmacother. 2007 May;8(7):1011-23
references.pmid: 17472546
references.citation: JAMA. 1997 Mar 12;277(10):813-7
references.pmid: 9052711
references.citation: Acta Neuropathol. 1991;82(4):239-59
references.pmid: 1759558
references.citation: Lancet. 2004 Jun 26;363(9427):2105-15
references.pmid: 15220031
references.citation: Curr Opin Neurobiol. 1995 Oct;5(5):663-8
references.pmid: 8580719
references.citation: Alzheimers Dement. 2007 Oct;3(4):355-84
references.pmid: 19595958
references.citation: Arch Neurol. 1997 Apr;54(4):465-73
references.pmid: 9109749
references.citation: Neurobiol Aging. 2008 Aug;29(8):1204-17
references.pmid: 17379359
references.citation: Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9
references.pmid: 9236950
references.citation: JAMA. 2004 Jan 21;291(3):317-24
references.pmid: 14734594
references.citation: Neurology. 2009 Sep 1;73(9):674-80
references.pmid: 19720973
references.citation: Exp Neurol. 1995 Feb;131(2):193-202
references.pmid: 7895820
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Neurology. 1994 Dec;44(12):2315-21
references.pmid: 7991118
references.citation: Neurology. 2001 May 8;56(9):1154-66
references.pmid: 11342679
references.citation: J Neuroimaging. 2006 Jan;16(1):16-23
references.pmid: 16483272
references.citation: Science. 1982 Mar 5;215(4537):1237-9
references.pmid: 7058341
references.citation: Neurotox Res. 2003;5(7):491-504
references.pmid: 14715433
references.citation: Clin Ther. 1989 Jul-Aug;11(4):545-54
references.pmid: 2776169
references.citation: Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003154
references.pmid: 16625572
references.citation: Brain. 2009 Sep;132(Pt 9):2356-71
references.pmid: 19605530
references.citation: J Clin Psychopharmacol. 2009 Apr;29(2):147-56
references.pmid: 19512976
references.citation: Curr Neuropharmacol. 2008 Jun;6(2):117-24
references.pmid: 19305792
references.citation: Lancet. 2002 Apr 13;359(9314):1283-90
references.pmid: 11965273
references.citation: Neurology. 2003 Jul 8;61(1):46-54
references.pmid: 12847155
references.citation: Science. 1993 Aug 13;261(5123):921-3
references.pmid: 8346443
references.citation: Neuron. 2003 May 22;38(4):547-54
references.pmid: 12765607
references.citation: Alzheimers Dement. 2007 Oct;3(4):398-403
references.pmid: 19595960
references.citation: J Am Geriatr Soc. 2005 Jul;53(7):1269-70
references.pmid: 16108961
references.citation: J Neuropathol Exp Neurol. 1997 Apr;56(4):321-39
references.pmid: 9100663
references.citation: Neurology. 2007 Dec 11;69(24):2197-204
references.pmid: 17568013
references.citation: Arch Neurol. 2008 Aug;65(8):1031-8
references.pmid: 18695053
references.citation: Arch Neurol. 1994 Jan;51(1):41-5
references.pmid: 8274108
references.citation: Drugs Aging. 2005;22(8):695-707
references.pmid: 16060719
references.citation: Neurobiol Aging. 2000 Mar-Apr;21(2):331-42
references.pmid: 10867218
references.citation: Arch Neurol. 2003 Dec;60(12):1685-91
references.pmid: 14676042
references.citation: J Am Geriatr Soc. 1996 Apr;44(4):411-5
references.pmid: 8636587
references.citation: CMAJ. 1994 Mar 15;150(6):899-913
references.pmid: 8131123
references.citation: Ann Neurol. 2008 Aug;64(2):168-76
references.pmid: 18496870
references.citation: N Engl J Med. 2007 Aug 30;357(9):933-5
references.pmid: 17761598
references.citation: Brain Res Bull. 2010 Jan 15;81(1):3-6
references.pmid: 19748552
references.citation: Brain Pathol. 1991 Apr;1(3):213-6
references.pmid: 1669710
references.citation: J Psychopharmacol. 2006 Nov;20(6):732-55
references.pmid: 17060346
references.citation: Lancet. 2004 Mar 6;363(9411):757-67
references.pmid: 15016485
references.citation: Cochrane Database Syst Rev. 2003;(3):CD001190
references.pmid: 12917900
references.citation: Nat Med. 1996 Aug;2(8):864-70
references.pmid: 8705854
references.citation: J Neurochem. 2006 Nov;99(3):689-707
references.pmid: 17076654
references.citation: Neurology. 2002 Aug 27;59(4):563-72
references.pmid: 12196650
references.citation: J Neural Transm Suppl. 1998;53:169-80
references.pmid: 9700655
references.citation: Neurodegeneration. 1996 Sep;5(3):213-8
references.pmid: 8910899
references.citation: Nat Med. 1996 Oct;2(10):1146-50
references.pmid: 8837617
references.citation: Cochrane Database Syst Rev. 2000;(4):CD001191
references.pmid: 11034705
references.citation: Am J Pathol. 1999 Sep;155(3):853-62
references.pmid: 10487842
references.citation: Clin Interv Aging. 2007;2(1):17-32
references.pmid: 18044073
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9649-53
references.pmid: 8415756
references.citation: Am J Psychiatry. 1984 Nov;141(11):1356-64
references.pmid: 6496779
references.citation: J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47
references.pmid: 10071091
references.citation: Drugs Aging. 2006;23(10):839-42
references.pmid: 17067186
references.citation: BMJ. 2009 Feb 05;338:b75
references.pmid: 19196746
references.citation: Curr Neuropharmacol. 2007;5(2):127-34
references.pmid: 18615180
references.citation: Brain. 2008 Dec;131(Pt 12):3299-310
references.pmid: 18953056
references.citation: Trends Neurosci. 1993 Nov;16(11):460-5
references.pmid: 7507619
references.citation: Nat Med. 2006 Jul;12(7):801-8
references.pmid: 16767098
references.citation: Lancet. 1998 Oct 24;352(9137):1347-51
references.pmid: 9802273
references.citation: Biochem J. 1997 May 1;323 ( Pt 3):577-91
references.pmid: 9169588
references.citation: Drugs Aging. 2009;26(5):403-7
references.pmid: 19552492
references.citation: Lancet. 2002 Nov 23;360(9346):1623-30
references.pmid: 12457784
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):227-31
references.pmid: 15615853
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: N Engl J Med. 2009 May 28;360(22):2357-9
references.pmid: 19474435
references.citation: Neurology. 2007 Jul 24;69(4 Suppl 1):S14-22
references.pmid: 17646619
references.citation: Lancet Neurol. 2008 Aug;7(8):683-9
references.pmid: 18614402
references.citation: Ann Intern Med. 2004 Apr 20;140(8):627-38
references.pmid: 15096334
references.citation: Stroke. 2002 Apr;33(4):1152-62
references.pmid: 11935076
references.citation: N Engl J Med. 2008 May 1;358(18):1887-98
references.pmid: 18378519
references.citation: Nat Med. 2002 Nov;8(11):1263-9
references.pmid: 12379850
references.citation: Neurology. 1981 Dec;31(12):1552-4
references.pmid: 7198209
references.citation: Am J Geriatr Pharmacother. 2005 Mar;3(1):39-49
references.pmid: 16089246
references.citation: Lancet Neurol. 2008 Jun;7(6):483-93
references.pmid: 18450517
references.citation: Lancet. 2008 Jul 19;372(9634):207-15
references.pmid: 18640457
references.citation: Science. 1996 Oct 4;274(5284):99-102
references.pmid: 8810256
references.citation: Ann Neurol. 1996 Aug;40(2):149-56
references.pmid: 8773595
references.citation: Ann Intern Med. 2008 Mar 4;148(5):379-97
references.pmid: 18316756
references.citation: Am J Geriatr Pharmacother. 2006;4 Suppl A:S9-S24; quiz S25-S28
references.pmid: 17157793
references.citation: Clin Interv Aging. 2008;3(2):211-25
references.pmid: 18686744
references.citation: Can J Neurol Sci. 2008 Sep;35(4):508-9
references.pmid: 18973072
references.citation: CMAJ. 2003 Sep 16;169(6):557-64
references.pmid: 12975222
references.citation: Neurology. 2007 Jul 24;69(4 Suppl 1):S23-8
references.pmid: 17646620
references.citation: Neurobiol Aging. 1981 Fall;2(3):205-8
references.pmid: 7312098
references.citation: Lancet Neurol. 2004 Mar;3(3):184-90
references.pmid: 14980533
references.citation: J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):315-9
references.pmid: 15716518
references.citation: Arch Intern Med. 2003 May 12;163(9):1069-75
references.pmid: 12742805
references.citation: Science. 2007 May 4;316(5825):750-4
references.pmid: 17478722
references.citation: Ann Neurol. 1999 Dec;46(6):860-6
references.pmid: 10589538
references.citation: Lancet Neurol. 2004 Oct;3(10):622-6
references.pmid: 15380159
references.citation: Neurodegener Dis. 2008;5(3-4):126-32
references.pmid: 18322369
references.citation: Brain. 2006 Nov;129(Pt 11):2840-55
references.pmid: 17018549
references.citation: J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7
references.pmid: 19204022
references.citation: Lancet. 2005 Dec 17;366(9503):2112-7
references.pmid: 16360788
references.citation: CMAJ. 2008 Jan 29;178(3):316-21
references.pmid: 18227452
references.citation: N Engl J Med. 2009 May 28;360(22):2302-9
references.pmid: 19474427
references.citation: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6990-5
references.pmid: 15867159
references.citation: Am J Geriatr Psychiatry. 2006 Jul;14(7):561-72
references.pmid: 16816009
references.citation: Neurobiol Dis. 1997;4(5):313-28
references.pmid: 9440120
references.citation: Arch Neurol. 2004 Mar;61(3):378-84
references.pmid: 15023815
references.citation: Am J Occup Ther. 1999 Sep-Oct;53(5):471-81
references.pmid: 10500855
references.citation: Ann Intern Med. 2008 Mar 4;148(5):370-8
references.pmid: 18316755
references.citation: FASEB J. 1995 Dec;9(15):1570-6
references.pmid: 8529836
references.citation: Lancet. 2008 Jul 19;372(9634):216-23
references.pmid: 18640458
references.citation: Neurology. 1999 Apr 12;52(6):1158-65
references.pmid: 10214737
references.citation: Neurology. 2006 Feb 28;66(4):602-4
references.pmid: 16505324
references.citation: Lancet. 2001 Jan 20;357(9251):169-75
references.pmid: 11213093