Hostname: page-component-586b7cd67f-dlnhk Total loading time: 0 Render date: 2024-11-25T12:02:06.557Z Has data issue: false hasContentIssue false

Emerging Therapeutics for Alzheimer's Disease: An Avenue of Hope

Published online by Cambridge University Press:  07 November 2014

Abstract

Emerging therapies for Alzheimer's disease offer hope to patients and their caregivers. Future treatments will probably include combination approaches with agents that modify amyloid processing, deposition, and clearance. One example, the AD vaccine, reduced amyloid burden and changed behavior in animal models of AD, but the human trial was halted when several subjects developed brain inflammation. Anti-inflammatory agents have epidemiologic support, but clinical trials have been disappointing, possibly related to inadequate study with anti-inflammatory agents that modify amyloid processing. Agents that target known cardiovascular risk factors, such as hypercholesterolemia, hypertension, and insulin resistance, have epidemiologic, preclinical, and clinical evidence to warrant further investigation. Heavymetal chelators, antioxidants, neurotrophic factors, glutaminergic modulators, and agents that modify hyper-phosphorylation of Tau are other approaches in research and development.

Type
Review
Copyright
Copyright © Cambridge University Press 2003

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.Henderson, S. Epidemiology of dementia. Ann Med Interne (Paris). 1998;149:181186.Google ScholarPubMed
2.Kukull, WA, Ganguli, M. Epidemiology of dementia: concepts and overview. Neurol Clin. 2000;18:923950.CrossRefGoogle ScholarPubMed
3.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;60:11191122.CrossRefGoogle ScholarPubMed
4.Roses, AD, Pangalos, MN. Drug development and Alzheimer disease. Am J Geriatr Psychiatry. 2003;11:123130.CrossRefGoogle ScholarPubMed
5.Samuels, SC, Davis, KL. Experimental approaches to cognitive disturbance in Alzheimer's disease. Harv Rev Psychiatry. 1998;6:1122.CrossRefGoogle ScholarPubMed
6.Samuels, SC, Davis, KL. Somatic treatment. In: Maj, M, Sartorius, N, eds. Dementia. vol.3. 2nd ed. Chichester, England: Wiley, John & Sons, Inc; 2002:199246.CrossRefGoogle Scholar
7.Samuels, SC, Davis, KL. Advances in the treatment of Alzheimer's disease. In: Weiner, MF, Lipton, AM, eds. Dementias: Diagnosis, Treatment, and Research. 3rd ed. Arlington, VA: American Psychiatric Publishing Inc.; 2003:453481.Google Scholar
8.Engelborghs, S, De Deyn, PP. The neurochemistry of Alzheimer's disease. Acta Neurol Belg. 1997;97:6784.Google ScholarPubMed
9.Bierer, LM, Haroutunian, V, Gabriel, S, et al. Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64:749760.CrossRefGoogle ScholarPubMed
10.Bartus, RT, Dean, RL 3rd, Beer, B, Lippa, AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408414.CrossRefGoogle ScholarPubMed
11.Davis, KL, Mohs, RC, Tinklenberg, JR, Hollister, LE, Pfefferbaum, A, Kopell, BS. Cholinomimetics and memory. The effect of choline chloride. Arch Neurol. 1980;37:4952.CrossRefGoogle ScholarPubMed
12.Davis, KL, Mohs, RC, Tinklenberg, JR, Pfefferbaum, A, Hollister, LE, Kopell, BS. Physostigmine: improvement of long-term memory processes in normal humans. Science. 1978;201:272274.CrossRefGoogle ScholarPubMed
13.Cummings, JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry. 2003;11:131145.CrossRefGoogle ScholarPubMed
14.Vasilescu, C, Alexianu, M, Dan, A. Delayed neuropathy after organophosphorus insecticide (Dipterex) poisoning: a clinical, electrophysiological and nerve biopsy study. J Neurol Neurosurg Psychiatry. 1984;47:543548.CrossRefGoogle ScholarPubMed
15.Schneider, LS. Metrifonate for Alzheimer's disease patients. J Clin Psychiatry. 2000;61:218219.CrossRefGoogle ScholarPubMed
16.Rogers, SL, Doody, RS, Mohs, RC, Friedhoff, LT, and the Donepezil Study Group. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Arch Intern Med. 1998;158:10211031.CrossRefGoogle ScholarPubMed
17.Tariot, PN, Cummings, JL, Katz, IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc. 2001;49:15901599.Google ScholarPubMed
18.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;57:613620.CrossRefGoogle ScholarPubMed
19.Farlow, M, Anand, R, Messina, J Jr, Hartman, R, Veach, J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol. 2000;44:236241.CrossRefGoogle ScholarPubMed
20.Birks, J, Grimley Evans, J, lakovidou, V, Tsolaki, M. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2000:CD001191.Google ScholarPubMed
21.Food and Drug Administration. Exelon (rivastigmine tartrate) Package insert disclaimer. Available at: http://www.fda.gov/med-watch/safety/2001/exelon.htm. Accessed October 15, 2003.Google Scholar
22.Giacobini, E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem Res. 2003;28:515522.CrossRefGoogle ScholarPubMed
23.Olin, J, Schneider, L. Galantamine for Alzheimer's disease. Cochrane Database Syst Rev. 2002:CD001747.Google ScholarPubMed
24.Bodick, NC, Offen, WW, Levey, Al, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54:465473.CrossRefGoogle ScholarPubMed
25.Higgins, JP, Flicker, L. Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev. 2000:CD001015.Google ScholarPubMed
26.Sahakian, B, Jones, G, Levy, R, Gray, J, Warburton, D. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatry. 1989;154:797800.CrossRefGoogle ScholarPubMed
27.Wilson, AL, Langley, LK, Monley, J, et al. Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacol Biochem Behav. 1995;51:509514.CrossRefGoogle ScholarPubMed
28.Potter, A, Corwin, J, Lang, J, Piasecki, M, Lenox, R, Newhouse, PA. Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology (Berl). 1999;142:334342.CrossRefGoogle ScholarPubMed
29.Maelicke, A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease. Dement Geriatr Cogn Disord. 2000;11 (suppl 1):1118.CrossRefGoogle ScholarPubMed
30.Farber, NB, Hanslick, J, Kirby, C, McWilliams, L, Olney, JW. Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. Neuropsychopharmacology. 1998;18:5762.CrossRefGoogle ScholarPubMed
31.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 Psychiatry. 1999;14:135146.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
32.Reisberg, B, Doody, R, Stoffler, A, Schmitt, F, Ferris, S, Mobius, HJ, and the Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:13331341.CrossRefGoogle ScholarPubMed
33.Tariot, PN, Farlow, MR, Grossberg, G, Gergel, I, Graham, S, Jin, J. PB-098 Memantine/Donepezil Dual Therapy is Superior to Placebo/Donepezil Therapy for Treatment of Moderate to Severe Alzheimer's Disease. Poster presented at: Annual Meeting of the International Psychogeriatric Association. August 17-22, 2003. Chicago, Illinois.Google Scholar
34.Johnson, SA, Simmon, VF. Randomized, double-blind, placebo-controlled international clinical trial of the Ampakine CX516 in elderly participants with mild cognitive impairment: a progress report. J Mol Neurosci. 2002;19:197200.CrossRefGoogle ScholarPubMed
35.Hardy, J, Selkoe, DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353356.CrossRefGoogle ScholarPubMed
36.Selkoe, DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999;399(6738 suppl):A23A31.CrossRefGoogle ScholarPubMed
37.Vassar, R, Bennett, BD, Babu-Khan, S, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735741.CrossRefGoogle ScholarPubMed
38.Li, YM, Xu, M, Lai, MT, et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689694.CrossRefGoogle Scholar
39.Maurer, K, Volk, S, Gerbaldo, H. Auguste D and Alzheimer's disease. Lancet. 1997;349:15461549.CrossRefGoogle Scholar
40.Wolozin, BL, Pruchnicki, A, Dickson, DW, Davies, P. A neuronal antigen in the brains of Alzheimer patients. Science. 1986;232:648650.CrossRefGoogle ScholarPubMed
41.Grundke-Iqbal, I, Iqbal, K, Tung, YC, Quinlan, M, Wisniewski, HM, Binder, LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:49134917.CrossRefGoogle ScholarPubMed
42.Hanger, DP, Hughes, K, Woodgett, JR, Brion, JP, Anderton, BH. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett. 1992;147:5862.CrossRefGoogle ScholarPubMed
43.Phiel, CJ, Wilson, CA, Lee, VM, Klein, PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423:435439.CrossRefGoogle ScholarPubMed
44. Alzheimer's Disease Cooperative Study. Valproate protocal. Available at: http://adcs.ucsd.edu/VP_Protocol.htm. Accessed October 15, 2003.Google Scholar
45.Evans, RM, Emsley, CL, Gao, S, et al. Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans. Neurology. 2000;54:240242.CrossRefGoogle ScholarPubMed
46.Notkola, IL, Sulkava, R, Pekkanen, J, et al. Serum total cholesterol, apolipoprotein E4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17:1420.CrossRefGoogle ScholarPubMed
47.Romas, SN, Tang, MX, Berglund, L, Mayeux, R. APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology. 1999;53:517521.CrossRefGoogle Scholar
48.Tan, ZS, Seshadri, S, Beiser, A, et al. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch Intern Med. 2003;163:10531057.CrossRefGoogle ScholarPubMed
49.Sparks, DL, Scheff, SW, Hunsaker, JC 3rd, Liu, H, Landers, T, Gross, DR. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol. 1994;126:8894.CrossRefGoogle ScholarPubMed
50.Mori, T, Paris, D, Town, T, et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J Neuropathol Exp Neurol. 2001;60:778785.CrossRefGoogle ScholarPubMed
51.Distl, R, Meske, V, Ohm, TG. Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol (Berl). 2001;101:547554.CrossRefGoogle ScholarPubMed
52.Frears, ER, Stephens, DJ, Walters, CE, Davies, H, Austen, BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999;10:16991705.CrossRefGoogle ScholarPubMed
53.Jick, H, Zornberg, GL, Jick, SS, Seshadri, S, Drachman, DA. Statins and the risk of dementia. Lancet. 2000;356:16271631.CrossRefGoogle ScholarPubMed
54.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;57:14391443.CrossRefGoogle ScholarPubMed
55.Rockwood, K, Kirkland, S, Hogan, DB, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59:223227.CrossRefGoogle ScholarPubMed
56.Fassbender, K, Simons, M, Bergmann, C, et al. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001;98:58565861.CrossRefGoogle ScholarPubMed
57.Refolo, LM, Pappolla, MA, LaFrancois, J, et al. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2001;8:890899.CrossRefGoogle Scholar
58.Sparks, DL, Connor, DJ, Browne, PJ, Lopez, JE, Sabbagh, MN. HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier. J Nutr Health Aging. 2002;6:324331.Google ScholarPubMed
59.Simons, M, Keller, P, Dichgans, J, Schulz, JB. Cholesterol and Alzheimer's disease: is there a link? Neurology. 2001;57:10891093.CrossRefGoogle ScholarPubMed
60.Meske, V, Albert, F, Richter, D, Schwarze, J, Ohm, TG. Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. Eur J Neurosci. 2003;17:93102.CrossRefGoogle ScholarPubMed
61.The Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:722.CrossRefGoogle Scholar
62. Statins/CLASP-AD study resources page. Alzheimer's Disease Cooperative Study website. Available at: http://adcs.ucsd.edu/Statins_Protocol.htm. Accessed September 25, 2003.Google Scholar
63.Knopman, D, Boland, LL, Mosley, T, et, al, and the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001;56:4248.CrossRefGoogle ScholarPubMed
64.Forette, F, Seux, ML, Staessen, JA, et, al, and the Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002;162:20462052.CrossRefGoogle ScholarPubMed
65.Crook, T, Wilner, E, Rothwell, A, Winterling, D, McEntee, W. Noradrenergic intervention in Alzheimer's disease. Psychopharmacol Bull. 1992;28:6770.Google ScholarPubMed
66.Sterling, J, Herzig, Y, Goren, T, et al. Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. J Med Chem. 2002;45:52605279.CrossRefGoogle Scholar
67.Watson, GS, Craft, S. The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs. 2003;17:2745.CrossRefGoogle ScholarPubMed
68.Watson, GS, Peskind, ER, Asthana, S, et al. Insulin increases CSF Aβ42 levels in normal older adults. Neurology. 2003b;60:18991903.CrossRefGoogle ScholarPubMed
69.Perry, T, Greig, NH. The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease. J Alzheimers Dis. 2002;4:487496.CrossRefGoogle ScholarPubMed
70.Breitner, JC, Welsh, KA, Helms, MJ, et al. Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995;16:523530.CrossRefGoogle ScholarPubMed
71.Andersen, K, Launer, LJ, Ott, A, Hoes, AW, Breteler, MM, Hofman, A. Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease? The Rotterdam Study. Neurology. 1995;45:14411445.CrossRefGoogle ScholarPubMed
72.Sainati, SM, Ingram, DM, Talwalker, S, et al. Results of a doubleblind, randomized, placebo-controlled study of celecoxib in the treatment of progression of Alzheimer's disease. Abstract presented at: Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy. abstract book 2000;180. April 58, 2000. Skoki, Ill.CrossRefGoogle Scholar
73.Aisen, PS, Schafer, KA, Grundman, M, et al, for the Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289:28192826.CrossRefGoogle ScholarPubMed
74.Rogers, J, Kirby, LC, Hempelman, SR, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;43:16091611.CrossRefGoogle ScholarPubMed
75.Weggen, S, Eriksen, JL, Das, P, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature. 2001;414:212216.CrossRefGoogle ScholarPubMed
76.De Strooper, B, Konig, G. An inflammatory drug prospect. Nature. 2001;414:159160.CrossRefGoogle ScholarPubMed
77.Aisen, PS, Davis, KL, Berg, JD, et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology. 2000;54:588593.CrossRefGoogle ScholarPubMed
78.Chandrasekharan, NV, Dai, H, Roos, KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002;99:1392613931.CrossRefGoogle ScholarPubMed
79.Miller, GD, Rejeski, WJ, Williamson, JD, et al. The ADAPT Investigators. The Arthritis, Diet, and Activity Promotion Trial (ADAPT): design, rationale, and baseline results. Control Clin Trials. 2003;24:462480.CrossRefGoogle ScholarPubMed
80.Schenk, D, Barbour, R, Dunn, W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173177.CrossRefGoogle ScholarPubMed
81.Arendash, GW, Gordon, MN, Diamond, DM, et al. Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory. DNA Cell Biol. 2001;20:737744.CrossRefGoogle ScholarPubMed
82.Dodart, JC, Bales, KR, Gannon, KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002;5:452457.CrossRefGoogle ScholarPubMed
83.Senior, K. Dosing in phase II trial of Alzheimer's vaccine suspended. Lancet Neurol. 2002;1:3.CrossRefGoogle ScholarPubMed
84.Orgogozo, JM, Gilman, S, Dartigues, JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:4654.CrossRefGoogle Scholar
85.Mathews, PM, Nixon, RA. Setback for an Alzheimer's disease vaccine: Lessons learned. Neurology. 2003;61:78.CrossRefGoogle ScholarPubMed
86.Hock, C, Konietzko, U, Streffer, JR, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003;38:547554.CrossRefGoogle ScholarPubMed
87.Berthon, G. Does human betaA4 exert a protective function against oxidative stress in Alzheimer's disease? Med Hypotheses. 2000;54:672677.CrossRefGoogle ScholarPubMed
88.Smith, MA, Drew, KL, Nunomura, A, et al. Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int. 2002;40:527531.CrossRefGoogle ScholarPubMed
89.Rottkamp, CA, Atwood, CS, Joseph, JA, Nunomura, A, Perry, G, Smith, MA. The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides. 2002;23:13331341.CrossRefGoogle ScholarPubMed
90.Ball, MJ. Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved? Can J Neurol Sci. 1982;9:303306.CrossRefGoogle ScholarPubMed
91.Libikova, H, Pogady, J, Wiedermann, V, Breier, S. Search for herpetic antibodies in the cerebrospinal fluid in senile dementia and mental retardation. Acta Virol. 1975;19:493495.Google ScholarPubMed
92.Wardlaw, JM, Sandercock, PA, Dennis, MS, Starr, J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806812.CrossRefGoogle ScholarPubMed
93.Butterfield, DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Rodic Res. 2002;36:13071313.CrossRefGoogle ScholarPubMed
94.Behl, C, Davis, J, Cole, GM, Schubert, D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun. 1992;186:944950.CrossRefGoogle ScholarPubMed
95.Sano, M, Ernesto, C, Thomas, RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336;12161222.CrossRefGoogle ScholarPubMed
96.Engelhart, MJ, Geerlings, MI, Ruitenberg, A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287:32233229.CrossRefGoogle ScholarPubMed
97.Morris, MC, Beckett, LA, Scherr, PA, et al. Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord. 1998;12:121126.CrossRefGoogle ScholarPubMed
98.Luchsinger, JA, Tang, MX, Shea, S, Mayeux, R. Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol. 2003;60:203208.CrossRefGoogle ScholarPubMed
99.Morris, MC, Evans, DA, Bienias, JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287:32303237.CrossRefGoogle Scholar
100.Masaki, KH, Losonczy, KG, Izmirlian, G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 2000;54:12651272.CrossRefGoogle Scholar
101.Laurin, D, Foley, DJ, Masaki, KH, White, LR, Launer, LJ. Vitamin E and C supplements and risk of dementia. JAMA. 2002;288:22662268.CrossRefGoogle Scholar
102. Mild cognitive impairment study. Alzheimer's Disease Cooperative Study website. Available at: http://adcs.ucsd.edu/MCI_Protocol.htm. Accessed September 25, 2003.Google Scholar
103.Seshadri, S, Beiser, A, Selhub, J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476483.CrossRefGoogle ScholarPubMed
104.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;55:14491455.CrossRefGoogle ScholarPubMed
105.Miller, JW, Green, R, Mungas, DM, Reed, BR, Jagust, WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology. 2002;58:14711475.CrossRefGoogle ScholarPubMed
106.Lipton, SA, Kim, WK, Choi, YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94:59235928.CrossRefGoogle ScholarPubMed
107.Ho, PI, Collins, SC, Dhitavat, S, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249253.CrossRefGoogle ScholarPubMed
108.Kruman, II, Kumaravel, TS, Lohani, A, 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;22:17521762.CrossRefGoogle ScholarPubMed
109.Miller, AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8:719.Google ScholarPubMed
110.Aisen, PS, Egelko, S, Andrews, H, et al. A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease. Am J Geriatr Psychiatry. 2003;11:246249.CrossRefGoogle ScholarPubMed
111.Le Bars, PL, Katz, MM, Berman, N, Itil, TM, Freedman, AM, Schatzberg, AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997;278:13271332.CrossRefGoogle ScholarPubMed
112.van Dongen, M, van Rossum, E, Kessels, A, Sielhorst, H, Knipschild, P. Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. J Clin Epidemiol. 2003;56:367376.CrossRefGoogle ScholarPubMed
113.Birks, J, Grimley, EV, Van Dongen, M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2002:CD003120.Google ScholarPubMed
114.Izzo, AA, Ernst, E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs. 2001;61:21632175.CrossRefGoogle ScholarPubMed
115.Martyn, CN, Barker, DJ, Osmond, C, Harris, EC, Edwardson, JA, Lacey, RE. Geographical relation between Alzheimer's disease and aluminum in drinking water. Lancet. 1989;1:5962.CrossRefGoogle ScholarPubMed
116.Bjertness, E, Candy, JM, Torvik, A, et al. Content of brain aluminum is not elevated in Alzheimer disease. Alzheimer Dis Assoc Disord. 1996;10:171174.CrossRefGoogle Scholar
117.Kawahara, M, Kato, M, Kuroda, Y. Effects of aluminum on the neurotoxicity of primary cultured neurons and on the aggregation of beta-amyloid protein. Brain Res Bull. 2001;55:211217.CrossRefGoogle ScholarPubMed
118.Campbell, A. The potential role of aluminium in Alzheimer's disease. Nephrol Dial Transplant. 2002;17 (suppl 2):1720.CrossRefGoogle ScholarPubMed
119.Crapper McLachlan, DR, Dalton, AJ, Kruck, TP, et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet. 1991;337:13041308.CrossRefGoogle ScholarPubMed
120.McLachlan, DR, Smith, WL, Kruck, TP. Desferrioxamine and Alzheimer's disease: video home behavior assessment of clinical course and measures of brain aluminum. Ther Drug Monit. 1993;15:602607.CrossRefGoogle ScholarPubMed
121.Savory, J, Huang, Y, Wills, MR, Herman, MM. Reversal by desferrioxamine of tau protein aggregates following two days of treatment in aluminum-induced neurofibrillary degeneration in rabbit: implications for clinical trials in Alzheimer's disease. Neurotoxicology. 1998;19:209214.Google ScholarPubMed
122.Perry, G, Sayre, LM, Atwood, CS, et al. The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications. CNS Drugs. 2002;16:339352.CrossRefGoogle ScholarPubMed
123.Bush, Al. Metal complexing agents as therapies for Alzheimer's disease. Neurobiol Aging. 2002;23:10311038.CrossRefGoogle ScholarPubMed
124.Cherny, RA, Atwood, CS, Xilinas, ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001;30:665676.CrossRefGoogle ScholarPubMed
125.Golomb, J, Wisoff, J, Miller, DC, et al. Alzheimer's disease comorbidity in normal pressure hydrocephalus: prevalence and shunt response. J Neurol Neurosurg Psychiatry. 2000;68:778781.CrossRefGoogle ScholarPubMed
126.Silverberg, GD, Levinthal, E, Sullivan, EV, et al. Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study. Neurology. 2002;59:11391145.CrossRefGoogle ScholarPubMed
127.Paganini-Hill, A, Henderson, VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996;156:22132217.CrossRefGoogle ScholarPubMed
128.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;288:21232129.CrossRefGoogle ScholarPubMed
129.Mulnard, RA, Cotman, CW, Kawas, C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer's disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000;283:10071015.CrossRefGoogle ScholarPubMed
130.Shumaker, SA, Legault, C, Rapp, SR, et, al, and the WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:26512662.CrossRefGoogle ScholarPubMed
131.Nickelsen, T, Lufkin, EG, Riggs, BL, Cox, DA, Crook, TH. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology. 1999;24:115128.CrossRefGoogle ScholarPubMed
132.Panisset, M, Gauthier, S, Moessler, H, Windisch, M, and the Cerebrolysin Study Group. Cerebrolysin in Alzheimer's disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm. 2002;109:10891104.CrossRefGoogle ScholarPubMed
133.Grundman, M, Capparelli, E, Kim, HT, for the Alzheimer's Disease Cooperative Study. A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin) in mild Alzheimer's disease patients. Life Sci. 2003;73:539553.CrossRefGoogle ScholarPubMed
134.Eriksdotter Jonhagen, M, Nordberg, A, Amberla, K, et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 1998;9:246257.CrossRefGoogle ScholarPubMed