Review Article
Treatments for Alzheimer Disease
Abstract
As our population ages, the incidence and prevalence of Alzheimer disease (AD) will increase dramatically. A number of therapies have been investigated for the treatment and prevention of AD. Clinicians should be prepared to provide evidence-based answers to inquiries regarding AD treatment. There is insufficient evidence to recommend ginkgo biloba, estrogen, statins, or nonsteroidal anti-inflammatory drugs for the prevention or treatment of AD. The use of vitamin E is supported by a single randomized controlled trial, while data on other antioxidants is mixed. There is good evidence that cholinesterase inhibitors and memantine are modestly effective in the treatment of AD. Cholinesterase inhibitors appear to be effective throughout the spectrum of AD, while memantine, alone or in combination with cholinesterase inhibitors, is effective in late stage disease. There is insufficient evidence to suggest superiority of one cholinesterase over another.This content is limited to qualifying members.
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References
1. Ott A, Breteler MM, van Harkskamp F, et al. Incidence and risk of dementia: The Rotterdam Study.Am J Epidemiol 1998;147:574–580.
2. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998;88:1337–1342.
3. Preventive Services Task Force. Screening for dementia: recommendation and rationale. Ann Int Med2003;138:925–926.
4. Boustani M, Peterson B, Hanson L, et al. Screening for dementia in primary care: a summary of the evidence for the U.S. preventive services task force. Ann Int Med 2003:138;927–937.
5. Lopez OL, Litvan I, Catt KE, et al. Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 1999;53:1292.
6. Geldmacher DS, Whitehouse PJ Jr. Differential diagnosis of Alzheimer's disease. Neurology1997;48:S2–S9.
7. Kaye JA. Diagnostic challenges in dementia. Neruology 1998;51:S4–52.
8. Farlow MR. Alzheimer's disease: clinical implications of the apolipoprotein E genotype. Neurology1997;48:S30–S34.
9. Bassuk SS, Glass TA, Berkman LF. Social disengagement and incident cognitive decline in community-dwelling elderly persons. Ann Int Med 1999;131:165–173.
10. Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and the risk of incident Alzheimer disease. JAMA 2002;287:742–748.
11. Fabrigoule C, Letenneur L, Dartigues JF, et al. Social and leisure activities and risk of dementia: a prospective longitudinal study. J Am Geriatr Soc 1995;43:485–490.
12. Verghese J, Lipton RB, Katz MJ, et al. Leisure activity and the risk of dementia in the elderly. NEJM2003;348:2508–2516.
13. Baines S, Saxby P, Ehlert K. Reality orientation and reminiscence therapy: a controlled cross-over study of elderly confused people. Br Journal of Psychology 1987;151:222–231.
14. Goldwasser AN, Auerbach SM, Harkins SW. Cognitive, affective and behavioural effects of reminiscence therapy on demented elderly. Int J Aging and Human Development 1987;25:209–222.
15. LeBaars PL, Katz MM, Berman N, et al. A placebo-controlled, double blind, randomized trial of an extract of ginkgo biloba for dementia. JAMA 1997;278:1327–1332.
16. Oken BS, Storzbach DM, Kaye JA. Efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurology 1998;55:1409–1415.
17. van Dongen MC, van Rossum E, Kessels AG, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 2000;48:1183–1194.
18. Solomon PR, Adams F, Silver A, et al. Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002;288:835–840.
19. Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different ginkgo biloba brands. J Pharm Pharmacol 2002;54:661–669.
20. Weiland N, Orikasa C, Hayashi S, et al. Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats. J Comp Neurol 1997;388:603–12.
21. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 1998;4:447–451.
22. Goodman Y, Bruce AJ, Cheng B, et al. Estrogens attenuate and corticosteroid exacerbates exitotoxicity, oxidative injury and amyloid B-peptide toxicity in hippocampal neurons. J Neurochem1996;66:1836–1844.
23. McEwen BS. Clinical review 108. The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 1999;84:1790–1797.
24. Fillit HM. The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Int Med 2002;162:1934–1942.
25. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age of onset of Alzheimer's disease. Lancet 1996;348:429–432.
26. Kawas C, Resnick S. Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore longitudinal study of aging. Neurology1997;48:1517–1521.
27. LeBlanc ES, Janowsky J, Chan BKS, et al. Hormone replacement therapy and cognition. Systematic review and meta-analysis. JAMA 2001;285:1489–99.
28. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 2002;288:2123–2129.
29. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13:345–357.
30. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women.Psychoneuroendocrinology 1992;17:485–495.
31. Binder EF, Schechtman KB, Birge SJ, et al. Effects of HRT on cognitive performance in elderly women. Maturitas 2001;38:137–146.
32. Shaywitz SE, Shaywitz BE, Pugh KR, et al. Effects of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999;281:1197–1202.
33. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA 2000;283:1007–1015.
34. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54:295–301.
35. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000;54:2061–2066.
36. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the women's health initiative randomized controlled trial. JAMA 2002;288:321–333.
37. Shumaker SA, Legault C, Rapp SR et al. Effect of estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women's health initiative study: a randomized controlled trial. JAMA 2003;289:2651–2662.
38. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947–2958.
39. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2959–2968.
40. Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. JAMA 2001;344:1207–1213.
41. Strittmatter WJ, Weisgraber KH, Huang Dy, et al. Binding of human aplipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993;90:8098–8102.
42. Richey PL, Siedlak SL, Smith MA, et al. Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer Disease: implications for disease pathogenesis. Biochem Biophys Res Commun 1995;208:657–663.
43. Wolozin B, Kellman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arch Neurol 2000;57:1439–1443.
44. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet 2000;356:1627–1631.
45. McGeer PL, McGeer EG. The inflammatory response system of the brain: implications for therapy in Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195–218.
46. 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.
47. Zandi PP, Breitner JC. Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging 2001;22:811–817.
48. Beard CM, Waring SC, O'Brien PC, et al. Nonsteroidal anti-inflammatory drug use and Alzheimer's disease: a case control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc1998;73:951–955.
49. In't Veld BA, Launer LJ, Hoes AW, et al. NSAIDs and incident Alzheimer's disease: The Rotterdam Study. Neurobiol Aging 1998;19:607–11.
50. Stewart WF, Kawas C, Corrada M, et al. Risk of Alzheimer's disease and duration of NSAID use.Neurology 1997;48:626–632.
51. In't Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. NEJM 2001;345:1515–1521.
52. 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;62:66–71.
53. Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression. A Randomized Controlled Trial JAMA 2003;289:2819–2826.
54. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer's disease.Neurology 1993;43:1609–1611.
55. Scharf S, Mander A, Ugoni A, et al. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 1999;53:197–201.
56. Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003;112:440–449.
57. Smith MA, Perry G, Richey PL, et al. Oxidative damage in Alzheimer's. Nature 1996;382:120–1.
58. Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540–10543.
59. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223–3229.
60. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alcheimer disease in a biracial community study. JAMA 2002;287:3230–3237.
61. Zandi PR, Anthony JC, Khachaturian AS, et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements. The Cache County Study. Arch Neurology 2004;61:82–88.
62. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol or both as treatment for Alzheimer's disease. NEJM 1997;336:1216–1222.
63. McGeer PL, McGeer EG, Suzuki J, et al. Aging, Alzheimer's disease, and the cholinergic system in the basal forebrain. Neurology 1984;34:741–745.
64. Rossor MN, Iversen LL, Reynolds GP, et al. Neurochemical characteristics of early and late onset types of Alzheimer's disease. BMJ 1984;288:961–964.
65. Arai H, Ichimiya Y, Kosaka K, et al. Neurotransmitter changes in early- and late-onset Alzheimer type dementia. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:883–890.
66. 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.
67. Sadot E, Gurwitz D, Barg J, et al. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem 1996;66:877–880.
68. Davis KL, Thal LJ, Gamzu ER, et al. A double blind, placebo-controlled multicenter study of tacrine for Alzheimer disease. The Tacrine Collaborative Study Group. NEJM 1992;327:1253–1259.
69. Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group. JAMA 1992;268:2523–2529.
70. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA 1994;271:985–991.
71. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology 1996;47:166–177.
72. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group Neurology 1998;50:1136–1145.
73. Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Int Med 1998;158:1021–1031.
74. Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer disease. Results from a multinational trial. Dementia and Geriatr Cogn Disorders 1999;10:237–244.
75. 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;57:489–495.
76. Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function study of donepezil in AD patients. Neurology 2001;57:481–488.
77. Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57:613–620.
78. Geldmacher DS, Provenzano G, McRae, et al. Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc 2003;51:937–944.
79. Cummings JL, Donahue JA, Brooks RL. Ther between donepezil and behavioral disturbances in patients with Alzheimer's disease. Am J. Geriatr Psych 2000;8:134–140.
80. Corey-Bloom J, Anand R, Veach J, for ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998;1:55–65.
81. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;319:633–638.
82. Farlow M, Anand R, Messina J, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 2000;46:236–241.
83. Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology2000;54:2261–2268.
84. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269–2276.
85. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer disease: multicentre randomized trial. BMJ 2000;321:1445–1449.
86. Aerssens J, Raeymaekers P, Lilienfeld S, et al. APOE genotype: no influence on glantamine treatment efficacy nor on rate of decline in Alzheimer's disease. Dementia Geriatric Cognitive Disorders2001;12:69–77.
87. AD2000 Collaborative Group. Long-term treatment in 656 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–2115.
88. Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease. Neurology 1999;25:1138–1145.
89. Livingston G, Katona C. How useful are cholinesterase inhibitors in the treatment of Alzheimer's disease? A number needed to treat analysis. Int J Geriatr Psychiatry 2000;15:203–207.
90. Enz A, Boddeke H, Gray J, et al. Pharmacologic and clinicopharmacologic properties of SDZ ENA 713, a centrally selective acetylcholinesterase inhibitor. Ann NY Acad Sci 1991;640:272–275.
91. Maelicke A, Samochocki M, Jostock R, et al. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease. Biol Psychiatry 2001;49:279–288.
92. Wilkinson D, Passmore P, Bullock R, et al. A multinational, randomized, 12-week comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. Int J Clin Practice 2002;56:441–446.
93. Jones RW, Soininen H, Hager K, et al. First head-to-head study comparing the tolerability, ease of use and efficacy of donepezil and galantamine in Alzheimer's disease. Poster Presentation at: The 7thInternational Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT); April 4, 2002; Geneva, Switzerland.
94. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzhiemer's disease: a compariason of tolerability and pharmacology. Drug Safety 1998;19:465–480.
95. Butterfield DA, Pocernich CB. The glutamatergic system and Alzheimer's disease: therapeutic implications. CNS Drugs 2003;17:641–652.
96. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Pysch1999;14:135–146.
97. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer disease. NEJM2003;348:1333–1341.
98. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA2004;291:317–324.
99. Sobow TM, Kloszewska I, Karlinska I. Addition of vitamin E to donepezil as a treatment for Alzheimer's disease. Alzheimer's Reports 1999;2:143–146.
100. Rigaud AS, Andre G, Vellas B, et al. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology 2003;60:148–149.
