Disease-modifying therapies for Alzheimer disease: Challenges to early intervention

Neurology

Volumn 69, Issue 16, 2007, Pages 1622-1634

  Cummings, Jeffrey L ^a,d   Doody, Rachelle ^b   Clark, Christopher ^c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; AMYLOID BETA PROTEIN; ANTIARRHYTHMIC AGENT; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; BETA SECRETASE INHIBITOR; BIOLOGICAL MARKER; CASPASE INHIBITOR; CHOLINERGIC RECEPTOR STIMULATING AGENT; CHOLINESTERASE INHIBITOR; DONEPEZIL; GALANTAMINE; GAMMA SECRETASE INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MONOAMINE OXIDASE INHIBITOR; MUSCARINIC AGENT; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NERVE GROWTH FACTOR; NEUROTROPHIN; PIRACETAM; PLACEBO; RIVASTIGMINE; ROFECOXIB; TAU PROTEIN;

ALZHEIMER DISEASE; BRAIN ATROPHY; CELL THERAPY; CLINICAL TRIAL; DISEASE MARKER; HUMAN; IMMUNIZATION; INTERVENTION STUDY; NEUROPATHOLOGY; NEUROPSYCHOLOGICAL TEST; NUCLEAR MAGNETIC RESONANCE IMAGING; POSITRON EMISSION TOMOGRAPHY; PRIMARY PREVENTION; PRIORITY JOURNAL; PROTEIN CEREBROSPINAL FLUID LEVEL; REVIEW; SECONDARY PREVENTION; STEM CELL TRANSPLANTATION; TEMPORAL LOBE; AGED; BRAIN; DIAGNOSTIC IMAGING; DRUG SCREENING; EARLY DIAGNOSIS; METABOLISM; MIDDLE AGED; PATHOPHYSIOLOGY; PREDICTION AND FORECASTING; RISK FACTOR; STANDARD;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; BIOLOGICAL MARKERS; BRAIN; CLINICAL TRIALS; DIAGNOSTIC IMAGING; DRUG EVALUATION, PRECLINICAL; EARLY DIAGNOSIS; HUMANS; MIDDLE AGED; NEUROPSYCHOLOGICAL TESTS; PREDICTIVE VALUE OF TESTS; RISK FACTORS;

EID: 35848962080     PISSN: 00283878     EISSN: None     Source Type: Journal    
DOI: 10.1212/01.wnl.0000295996.54210.69     Document Type: Review

References (158)

1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-356.
2. Li R, Lindholm K, Yang LB, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA 2004;101:3632-3637.
3. McLean CA, Cherny RA, Fraser FW, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999;46:860-866.
4. Selkoe DJ. Presenilins, beta-amyloid precursor protein and the molecular basis of Alzheimer's disease. Clin Neurosci Res 2001;1:91-103.
5. Lesne S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352-357.
6. Cummings JL. Drug therapy: Alzheimer's disease. N Engl J Med 2004;351:56-67.
7. Roher AE, Weiss N, Kokjohn TA, 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.
8. Citron M. Strategies for disease modification in Alzheimer's disease. Nat Rev Neurosci 2004;5:677-685.
9. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol 2003;2:539-547.
10. Seiffert D, Bradley JD, Rominger CM, et al. Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J Biol Chem 2000;275:34086-34091.
11. Cummings JL. Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials. Alzheimers Dementia (in press).
12. McConnell S, Riggs J. Alzheimer's research: can it help save our nation's entitlement programs? Alzheimer Dementia 2005;1:84-86.
13. Thal LJ, Carta A, Doody R, et al. Prevention protocols for Alzheimer disease: position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11(suppl 3):46-49.
14. Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66:1837-1844.
15. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Neurology 1987;43:465-479.
16. Jack CR Jr, Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999;52:1397-1403.
17. Tuokko H, Frerichs R, Graham J, et al. Five-year follow-up of cognitive impairment with no dementia. Arch Neurol 2003;60:577-582.
18. Linn RT, Wolf PA, Bachman DL, et al. The "preclinical phase" of probable Alzheimer's disease: a 13-year prospective study of the Framingham cohort. Arch Neurol 1995;52:485-490.
19. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L. The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. Arch Neurol 2000;57:839-844.
20. Tierney MC, Yao C, Kiss A, McDowell I. Neuropsychological tests accurately predict incident Alzheimer disease after 5 and 10 years. Neurology 2005;64:1853-1859.
21. Cummings JL. Clinical evaluation as a biomarker for Alzheimer's disease. J Alzheimers Dis 2005;8:327-337.
22. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-923.
23. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61:661-666.
24. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187-1192.
25. Cupples LA, Farrer LA, Sadovnick AD, Relkin N, Whitehouse P, Green RC. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet Med 2004;6:192-196.
26. Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia Aging Study. Neurobiol Aging 2000;21:49-55.
27. Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood pressure and the risk of dementia in very old individuals. Neurology 2003;61:1667-1672.
28. Qiu C, von Strauss E, Fastbom J, Winblad B, Fratiglioni L. Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol 2003;60:223-228.
29. van Osch LA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease. Neurology 2004;62:1967-1971.
30. Ott A, Andersen K, Dewey ME, et al. Effect of smoking on global cognitive function in nondemented elderly. Neurology 2004;62:920-924.
31. Honig LS, Tang MX, Albert S, et al. Stroke and the risk of Alzheimer disease. Arch Neurol 2003;60:1707-1712.
32. Graves AB, Mortimer JA, Bowen JD, et al. Head circumference and incident Alzheimer's disease. Neurology 2001;57:1453-1460.
33. Schofield PW, Logroscino G, Andrews HF, Albert S, Stern Y. An association between head circumference and Alzheimer's disease in a population-based study of aging and dementia. Neurology 1997;49:30-37.
34. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002;33:2351-2356.
35. Pappolla MA, Bryant-Thomas TK, Herbert D, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 2003;61:199-205.
36. Shobab LA, Hsiung GY, Feldman HH. Cholesterol in Alzheimer's disease. Lancet Neurol 2005;4:841-852.
37. ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT). Available at: http://www.plosclinicaltrials.org. Accessed August 16, 2007.
38. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 2006;5:735-741.
39. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry 2000;157:4-15.
40. Godbolt AK, Cipolotti L, Anderson VM, et al. A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia. Neurocase 2005;11:56-64.
41. Lind J, Persson J, Ingvar M, et al. Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers. Brain 2006;129:1240-1248.
42. Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med 2000;343:450-456.
43. Bassett SS, Yousem DM, Cristinzio C, et al. Familial risk for Alzheimer's disease alters fMRI activation patterns. Brain 2006;129:1229-1239.
44. Moonis M, Swearer JM, Dayaw MP, et al. Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology 2005;65:323-325.
45. Peskind ER, Li G, Shofer J, et al. Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol 2006;63:936-939.
46. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39:168-177.
47. van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM. Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 2006;5:655-660.
48. Nordberg A. PET imaging of amyloid in Alzheimer's disease. Lancet Neurol 2004;3:519-527.
49. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-319.
50. Shoghi-Jadid K, Small GW, Agdeppa ED, 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.
51. Verhoeff NP, Wilson AA, Takeshita S, et al. In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12:584-595.
52. Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355:2652-2663.
53. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 2006;59:512-519.
54. Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 2001;56:37-42.
55. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388.
56. Grundman M, Petersen RC, Ferris SH, et al. Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 2004;61:59-66.
57. Alexopoulos P, Grimmer T, Perneczky R, Domes G, Kurz A. Progression to dementia in clinical subtypes of mild cognitive impairment. Dement Geriatr Cogn Disord 2006;22:27-34.
58. Jelic V, Kivipelto M, Winblad B. Clinical trials in mild cognitive impairment: lessons for the future. J Neurol Neurosurg Psychiatry 2006;77:429-438.
59. 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.
60. Hwang TJ, Masterman DL, Ortiz F, Fairbanks LA, Cummings JL. Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms. Alzheimer Dis Assoc Disord 2004;18:17-21.
61. Chong MS, Sahadevan S. Preclinical Alzheimer's disease: diagnosis and prediction of progression. Lancet Neurol 2005;4:576-579.
62. Jicha GA, Parisi JE, Dickson DW, et al. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 2006;63:674-681.
63. Kryscio RJ, Schmitt FA, Salazar JC, Mendiondo MS, Markesbery WR. Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006;66:828-832.
64. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240-246.
65. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet 2006;367:1262-1270.
66. Pennanen C, Kivipelto M, Tuomainen S, et al. Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 2004;25:303-310.
67. Becker JT, Davis SW, Hayashi KM, et al. Threedimensional patterns of hippocampal atrophy in mild cognitive impairment. Arch Neurol 2006;63:97-101.
68. Killiany RJ, Gomez-Isla T, Moss M, et al. Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol 2000;47:430-439.
69. DeCarli C, Frisoni GB, Clark CM, 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.
70. Apostolova LG, Dutton RA, Dinov ID, et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol 2006;63:693-699.
71. Jack CR Jr, Slomkowski M, Gracon S, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 2003;60:253-260.
72. 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.
73. Ewers M, Teipel SJ, Dietrich O, et al. Multicenter assessment of reliability of cranial MRI. Neurobiol Aging 2006;27:1051-1059.
74. Falini A, Bozzali M, Magnani G, et al. A whole brain MRspectroscopy study from patients with Alzheimer's disease and mild cognitive impairment. Neuroimage 2005;26:1159-1163.
75. Metastasio A, Rinaldi P, Tarducci R, et al. Conversion of MCI to dementia: role of proton magnetic resonance spectroscopy. Neurobiol Aging 2006;27:926-932.
76. Kantarci K, Jack CR Jr, Xu YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: a 1H MRS study. Neurology 2000;55:210-217.
77. Machulda MM, Ward HA, Borowski B, et al. Comparison of memory fMRI response among normal, MCI, and Alzheimer's patients. Neurology 2003;61:500-506.
78. Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol 2003;60:393-398.
79. Bartzokis G, Sultzer D, Lu PH, Nuechterlein KH, Mintz J, Cummings JL. Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical "disconnection" in aging and Alzheimer's disease. Neurobiol Aging 2004;25:843-851.
80. De Santi S, de Leon MJ, Rusinek H, et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging 2001;22:529-539.
81. Nestor PJ, Fryer TD, Smielewski P, Hodges JR. Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment. Ann Neurol 2003;54:343-351.
82. Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC. Mild cognitive impairment: can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology 2003;60:1374-1377.
83. Devanand DP, Habeck CG, Tabert MH, et al. PET network abnormalities and cognitive decline in patients with mild cognitive impairment. Neuropsychopharmacology 2006;31:1327-1334.
84. Jagust W, Gitcho A, Sun F, Kuczynski B, Mungas D, Haan M. Brain imaging evidence of preclinical Alzheimer's disease in normal aging. Ann Neurol 2006;59:673-681.
85. Johnson KA, Jones K, Holman BL, et al. Preclinical prediction of Alzheimer's disease using SPECT. Neurology 1998;50:1563-1571.
86. Cagnin A, Brooks DJ, Kennedy AM, et al. In-vivo measurement of activated microglia in dementia. Lancet 2001;358:461-467.
87. Kepe V, Barrio JR, Huang SC, et al. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc Natl Acad Sci USA 2006;103:702-707.
88. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 2003;289:2094-2103.
89. Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol 2003;2:605-613.
90. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228-234.
91. Peskind ER, Riekse R, Quinn JF, et al. Safety and acceptability of the research lumbar puncture. Alzheimer Dis Assoc Disord 2005;19:220-225.
92. Thal LJ, Kantarci K, Reiman EM, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:6-15.
93. Aisen PS, Saumier D, Briand R, et al. A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology 2006;67:1757-1763.
94. Montine TJ, Quinn JF, Montine KS, Kaye JA, Breitner JC. Quantitative in vivo biomarkers of oxidative damage and their application to the diagnosis and management of Alzheimer's disease. J Alzheimers Dis 2005;8:359-367.
95. Maruyama M, Higuchi M, Takaki Y, et al. Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease. Ann Neurol 2005;57:832-842.
96. Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672.
97. Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 2003;60:729-736.
98. Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR. Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006;63:38-46.
99. Mitchell TW, Mufson EJ, Schneider JA, et al. Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease. Ann Neurol 2002;51:182-189.
100. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol 1999;45:358-368.
101. Kordower JH, Chu Y, Stebbins GT, et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001;49:202-213.
102. Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol 2005;58:730-735.
103. Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging 2006;27:1094-1099.
104. Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11 (suppl 2):S13-21.
105. Leber P. Guidelines for the clinical evaluation of antidementia drugs. Washington, DC: Food and Drug Administration, 1990.
106. Rang HP. Drug development: introduction. In: Rang HP, ed. Drug discovery and development. New York: Churchill Livingston, 2006:221-228.
107. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-177.
108. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-1562.
109. Roberds SL, Anderson J, Basi G, 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.
110. Schmidt B, Baumann S, Braun HA, Larbig G. Inhibitors and modulators of beta- and gamma-secretase. Curr Top Med Chem 2006;6:377-392.
111. Lanz TA, Himes CS, Pallante G, 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.
112. Siemers ER, Quinn JF, Kaye J, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006;66:602-604.
113. 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.
114. Gervais F, Paquette J, Morissette C, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 2007;28:537-547.
115. Aisen P, Gauthier S, Vellas B, et al.. Tramiprosate (Alzhemed ™): a potential treatment for Alzheimer's disease. In: 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy; April 22, 2006; Geneva, Switzerland.
116. 40 in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:5856-5861.
117. Simons M, Schwarzler F, Lutjohann D, 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.
118. 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.
119. Watson GS, Cholerton BA, Reger MA, 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.
120. 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;30:665-676.
121. Ritchie CW, Bush AI, Mackinnon A, 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.
122. Dedeoglu A, Cormier K, Payton S, et al. Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis. Exp Gerontol 2004;39:1641-1649.
123. Fisher A, Brandeis R, Bar-Ner RH, et al. AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease. J Mol Neurosci 2002;19:145-153.
124. Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 2006;49:671-682.
125. 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.
126. Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001;24:1217-1281.
127. Williams LR, Varon S, Peterson GM, et al. Continuous infusion of nerve growth factor prevents basal fore-brain neuronal death after fimbria fornix transection. Proc Natl Acad Sci USA 1986;83:9231-9235.
128. 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.
129. Sung S, Yao Y, Uryu K, 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.
130. 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;336:1216-1222.
131. Asano T, Mori T, Shimoda T, 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.
132. US National Institutes of Health. Available at: http://www. clinicaltrials.gov/ct/show/NCT00083421?0rder=11. Accessed August 16, 2007.
133. de Paulis T. ONO 2506. Ono Curr Opin Investig Drugs 2003;4:863-867.
134. 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;22:1752-1762.
135. 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;11:246-249.
136. Finch EC, Longo V, Miyao A, et al.. Inflammation in Alzheimer's disease. In: Chesselet M-F, ed. Molecular mechanisms of neurodegenerative diseases. Totowa, NJ: Humana Press, 2001:87-110.
137. 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.
138. 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.
139. Quirk JC, Nisenbaum ES. LY404187: a novel positive allosteric modulator of AMPA receptors. CNS Drug Rev 2002;8:255-282.
140. 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.
141. AMRAKINE® fixed-dose CX516 cross national study of mild cognitive impairment (MCI) fails to meet primary endpoint. Available at: www.cortexpharm.com/html/news/o4/02-17-94.html. Accessed August 16, 2007.
142. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 2003;423:435-439.
143. Hong M, Chen DC, Klein PS, Lee VM. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 1997;272:25326-25332.
144. Gamblin TC, Chen F, Zambrano A, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA 2003;100:10032-10037.
145. 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.
146. 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.
147. Youdim MB, Bar Am O, Yogev-Falach M, et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res 2005;79:172-179.
148. Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol 2002;53:633-640.
149. Gatto GJ, Bohme GA, Caldwell WS, 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.
150. 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.
151. Sabbagh MN, Farlow MR, Relkin N, Beach TG. Do cholinergic therapies have disease-modifying effects in Alzheimer's disease? Alzheimers Dementia 2006;2:118-125.
152. Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:S12-S18.
153. Fournier J, Keane PE, Ferrara P, Soubrie P. SR57746A: an orally active non-peptide compound with neurotrophic and neuroprotective effects. CNS Drug Rev 1997;3:148-167.
154. 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.
155. Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005;11:551-555.
156. Labie C, Lafon C, Marmouget C, 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.
157. Sugaya K. Possible use of autologous stem cell therapies for Alzheimer's disease. Curr Alzheimer Res 2005;2:367-376.
158. Sugaya K, Alvarez A, Marutle A, Kwak YD, Choumkina E. Stem cell strategies for Alzheimer's disease therapy. Panminerva Med 2006;48:87-96.