Clinical trials and late-stage drug development for Alzheimer's disease: An appraisal from 1984 to 2014

Journal of Internal Medicine

Volumn 275, Issue 3, 2014, Pages 251-283

  Schneider, L S ^a   Mangialasche, F ^b,c   Andreasen, N ^b,d   Feldman, H ^e   Giacobini, E ^f   Jones, R ^g   Mantua, V ^h   Mecocci, P ^c   Pani, L ^h   Winblad, B ^b   Kivipelto, M ^b,i  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b KAROLINSKA INSTITUTE   (Sweden)

^c UNIVERSITY OF PERUGIA   (Italy)

^d KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^e UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^f UNIVERSITY OF GENEVA   (Switzerland)

^g UNIVERSITY OF BATH   (United Kingdom)

^h ITALIAN MEDICINES AGENCY   (Italy)

ⁱ UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

Alzheimer; Clinical trial; Dementia; Drug development; Treatment

Indexed keywords

ADUCANUMAB; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ANTIINFLAMMATORY AGENT; AVAGACESTAT; BAN 2401; BETA SECRETASE 1; BIOLOGICAL MARKER; CHOLINESTERASE INHIBITOR; GANTENERUMAB; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOGLOBULIN G; MEMANTINE; MONOAMINE OXIDASE INHIBITOR; MONOCLONAL ANTIBODY; MUSCARINIC M1 RECEPTOR AGONIST; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEUROPROTECTIVE AGENT; NOOTROPIC AGENT; SEROTONIN AGONIST; UNCLASSIFIED DRUG; VANUTIDE CRIDIFICAR;

ALZHEIMER DISEASE; ARTICLE; CHOLINERGIC NERVE CELL; CHOLINERGIC SYSTEM; CLINICAL DEMENTIA RATING; CLINICAL TRIAL (TOPIC); COMPETITIVE INHIBITION; DAILY LIFE ACTIVITY; DIET SUPPLEMENTATION; DISEASE COURSE; DISEASE SEVERITY; DRUG INDUSTRY; EPISODIC MEMORY; EXECUTIVE FUNCTION; HEALTH CARE POLICY; HISTORY OF MEDICINE; HUMAN; MEMORY DISORDER; META ANALYSIS (TOPIC); MEYNERT BASAL NUCLEUS; MILD COGNITIVE IMPAIRMENT; MINI MENTAL STATE EXAMINATION; NEUROPATHOLOGY; NEUROPSYCHOLOGICAL TEST; OUTCOME ASSESSMENT; PARKINSON DISEASE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PRODROMAL SYMPTOM; QUALITY ADJUSTED LIFE YEAR; SYSTEMATIC REVIEW (TOPIC); WECHSLER MEMORY SCALE;

ALZHEIMER; CLINICAL TRIAL; DEMENTIA; DRUG DEVELOPMENT; TREATMENT;

ALZHEIMER DISEASE; BIOLOGICAL MARKERS; CHOLINESTERASE INHIBITORS; DOPAMINE AGENTS; DRUG MONITORING; HUMANS; MEDICATION THERAPY MANAGEMENT; MEMANTINE; MEMORY DISORDERS; NOOTROPIC AGENTS; PRACTICE GUIDELINES AS TOPIC; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84895729886     PISSN: 09546820     EISSN: 13652796     Source Type: Journal    
DOI: 10.1111/joim.12191     Document Type: Article

References (157)

1. Becker RE, Greig NH, Giacobini E. Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices? J Alzheimers Dis 2008; 15: 303-25.
2. Lindner MD, McArthur RA, Deadwyler S, Hampson R, Tariot PN. Development, Optimization and Use of Preclinical Behavioral Models to Maximize the Productivity of Drug Discovery for Alzheimer's Disease. In: McArthur RA, Borsini F, eds. Animal and Translational Models for CNS Drug Discovery. San Diego: Academic Press, 2008; 93-157.
3. Pharmaceutical Research and Manufacturers of America. Researching Alzheimer's medicines: setbacks and stepping stones. 2012.
4. Giacobini E. Cholinesterases in human brain: the effect of cholinesterase inhibitors on Alzheimer's disease and related disorders. In: Giacobini E, Pepeu G, eds. The Brain Cholinergic System in Health and Disease Oxon. Oxon, UK: Informa Healthcare, 2006; 235-64.
5. Schneider LS. Issues in Design and Conduct of Clinical Trials for Cognitive-Enhancing Drugs. In: McArthur RA, Borsini F, eds. Animal and Translational Models for CNS Drug Discovery. San Diego: Academic Press, 2008; 21-76.
6. Food and Drug Administration Division of Neuropharmacological Drug Products. Tacrine as a treatment for Alzheimer's dementia. N Engl J Med 1991; 324: 349-52.
7. Davis KL, Thal LJ, Gamzu ER et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group [see comments]. N Engl J Med 1992; 327: 1253-9.
8. Murphy MF, Hardiman ST, Nash RJ et al. Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease. Ann N Y Acad Sci 1991; 640: 253-62.
9. Thal LJ, Schwartz G, Sano M et al. A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group. Neurology 1996; 47: 1389-95.
10. Olin JT, Schneider LS, Doody RS et al. Clinical evaluation of global change in Alzheimer's disease: identifying consensus. J Geriatr Psychiatry Neurol 1996; 9: 176-80.
11. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry 1984; 141: 1356-64.
12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939-44.
13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association Press, 1987.
14. Leber P. Guidelines for the Clinical Evaluation of Anti-Dementia Drugs, 1st draft. Rockville, MD: United States Food and Drug Administration, 1990.
15. Drachman DA, Leavitt J. Human memory and the cholinergic system: a relationship to aging? Arch Neurol 1974; 30: 113-21.
16. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease [letter]. Lancet 1976; 2: 1403.
17. Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976; 99: 459-96.
18. Coyle J, Price D, DeLong M. Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 1983; 219: 1184-90.
19. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991; 12: 383-8.
20. Golde TE, Schneider LS, Koo EH. Anti-Aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 2011; 69: 203-13.
21. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010; 9: 702-16.
22. 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: 1553-62.
23. United States Food and Drug Administration Peripheral and Central Nervous System Drugs Advisory Committee Meeting, July 7, 1989. Rockville, MD: Department of Health and Human Services, Public Health Service, Food and Drug Administration. 1989.
24. McArthur RA, Gray J, Schreiber R. Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials. Curr Opin Investig Drugs 2010; 11: 740-60.
25. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group [see comments]. J Am Med Assoc 1992; 268: 2523-9.
26. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group [see comments]. J Am Med Assoc 1994; 271: 985-91.
27. Thal LJ, Ferguson JM, Mintzer J, Raskin A, Targum SD. A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer's disease. Neurology 1999; 52: 1146-52.
28. Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca U, Thal LJ. Efficacy and safety of eptastigmine for the treatment of patients with Alzheimer's disease. Neurology 1999; 52: 700-8.
29. Imbimbo BPT, Troetel WM, Martelli P, Lucchelli F, the Eptastigmine Study Group. A 6-month double-blind, placebo-controlled trial of eptastigmine in Alzheimer's disease. Dement Geriatr Cogn Disord 2000; 11: 17-24.
30. Lopez-Arrieta JM, Schneider L. Metrifonate for Alzheimer's disease. Cochrane Database Syst Rev 2006; 19: CD003155.
31. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev 2006; 25: CD001190.
32. Birks J, Grimley EvansJ, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2009; 2: CD001191.
33. Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2006, Issue 1. Cochrane Database Syst Rev 2006; 1: CD001747.
34. Chatellier G, Lacomblez L. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. Groupe Francais d'Etude de la Tetrahydroaminoacridine [see comments]. BMJ 1990; 300: 495-9.
35. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer's disease [see comments]. Lancet 1991; 337: 989-92.
36. Schneider LS, Olin JT. Overview of clinical trials of hydergine in dementia [see comments]. Arch Neurol 1994; 51: 787-98.
37. Jones RW, Laake K, Øksengård AR. D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev 2002; 2: Art No. CD003153. doi: 101002/146518582002
38. Birks J, Flicker L. Selegiline for Alzheimer's disease. Cochrane Database Syst Rev 2003; 1: CD000442.
39. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006; 1: CD005593.
40. Loveman E, Green C, Kirby J et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease. Health Technol Assess 2006; 10: iii-iv, ix-xi, 1-160.
41. Takeda A, Loveman E, Clegg A et al. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int J Geriatr Psychiatry 2006; 21: 17-28.
42. Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011; 68: 991-98. doi: 10.1001/archneurol.2011.69.
43. Aisen PS, Davis KL, Berg JD et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study [see comment]. Neurology 2000; 54: 588-93.
44. Mulnard RA, Cotman CW, Kawas C et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. [Erratum appears in JAMA 2000 Nov 22-29;284(20):2597]. JAMA 2000; 283: 1007-15.
45. Hake A, Tariot P, Hochadel T, Schneider L, Lahiri DK, Farlow M. Apolipoprotein E genotype in a 48-week multicenter double-blind placebo-controlled transdermal selegiline trial in mild to moderate Alzheimer disease. J Neurosci 2001; 187: S55.
46. 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.
47. Aisen P, Schafer K, Grundman M et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289: 2819-26.
48. Soininen H, West C, Robbins J, Niculescu L. Long-term efficacy and safety of celecoxib in Alzheimer's disease. Dement Geriatr Cogn Disord 2007; 23: 8-21.
49. Thal LJ, Carta A, Clarke WR et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology 1996; 47: 705-11.
50. Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 2000; 55: 805-10.
51. 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. JAMA 1997; 278: 1327-32.
52. Thal LJ, Grundman M, Berg J et al. Idebenone treatment fails to slow cognitive decline in Alzheimer's disease. Neurology 2003; 61: 1498-502.
53. Amaducci L, Maurer K, Winblad B et al. A long-term, double-blind, placebo-controlled efficacy and safety study of nicergoline in patients with mild to moderate Alzheimer's disease. Eur Neuropsychopharmacol 1999; 9: S323-24.
54. Kittner B, RÖSsner M, Rother M. Clinical trials in dementia with propentofylline. Ann N Y Acad Sci 1997; 826: 307-16.
55. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol 2008; 7: 483-93.
56. Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML, On behalf of the MK-677 Protocol 30 Study Group. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology 2008; 71: 1702-8.
57. Medivation Inc. Medivation and Pfizer announce results from phase 3CONCERT trial of Dimebon in Alzheimer's disease [media release]. 2012 Jan 17 [online]. Available from URL: http://www.medivation.com. Accessed February 21, 2012.
58. Pfizer Inc., Medivation Inc. Pfizer and Medivation announce results from two phase 3 studies in Dimebon (latrepirdine) Alzheimer's disease clinical development program [media release]. 2010 Mar 4 [online]. Available from URL: http://www.pfizer.com. Accessed February 22, 2012.
59. Schneider LS, Farlow MR, Porsteinsson A, Shimakura A, Nakagawa M, Iwakami N. The neuroprotective and neurotrophic agent T-817MA for Alzheimer disease: randomized, double-blind, placebo-controlled proof of concept trial outcomes (O3-06-06). Alzheimers Dement 2013; 9: 530-31.
60. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-98.
61. Winblad B, Engedal K, Soininen H et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. [see comment]. Neurology 2001; 57: 489-95.
62. Mohs RC, Doody RS, Morris JC et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. [erratum appears in Neurology 2001 Nov 27;57(10):1942]. Neurology 2001; 57: 481-8.
63. 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. [see comment]. N Engl J Med 1997; 336: 1216-22.
64. Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982; 139: 1136-9.
65. Morris JC, McKeel DW Jr, Storandt M et al. Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology 1991; 41: 469-78.
66. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 303-8.
67. United States Food and Drug Administration Peripheral and Central Nervous System Drugs Advisory Committee, Mild Cognitive Impairment. 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/minutes/3724m1.html, (accessed 13 March 2001).
68. Petersen RC, Thomas RG, Grundman M et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. [see comment]. N Engl J Med 2005; 352: 2379-88.
69. Feldman HH, Ferris S, Winblad B et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. [see comment]. Lancet Neurol 2007; 6: 501-12.
70. Winblad B, Gauthier S, Scinto L et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008; 70: 2024-35.
71. Thal LJ, Ferris SH, Kirby L et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005; 30: 1204-15.
72. Smith AD, Smith SM, de Jager CA et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 2010; 5: e12244.
73. Jelic V, Kivipelto M, Winblad B. Clinical trials in mild cognitive impairment: lessons for the future. J Neurol Neurosurg Psychiatry 2006; 77: 429-38.
74. Salloway S, Ferris S, Kluger A et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004; 63: 651-7.
75. Doody RS, Ferris SH, Salloway S et al. Donepezil treatment of patients with MCI. Neurology 2009; 72: 1555-61.
76. Raschetti R, Albanese E, Vanacore N, Maggini M. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med 2007; 4: e338.
77. European Medicines Agency. Pre-authorisation evaluation of medicines for human use. Guideline on medicinal products for the treatment of Alzheimer's disease and other dementias CPMP/EWP/553/95 Rev. 1. 2008.
78. Schneider LS, Sano M. Current Alzheimer's disease clinical trials: methods and placebo outcomes. Alzheimers Dement 2009; 5: 388-97.
79. Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ. Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet 2001; 358: 455-60.
80. Feldman HH, Doody RS, Kivipelto M et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease. Neurology 2010; 74: 956-64.
81. Sano M, Bell KL, Galasko D et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 2011; 77: 556-63.
82. Aisen PS, Schneider LS, Sano M et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 2008; 300: 1774-83.
83. Quinn JF, Raman R, Thomas RG et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 2010; 304: 1903-11.
84. Douillet P, Orgogozo JM. What we have learned from the xaliproden Sanofi-aventis trials. J Nutr Health Aging 2009; 13: 365-66.
85. Aisen PS, Gauthier S, Vellas B et al. Alzhemed: a potential treatment for Alzheimers disease. Curr Alzheimer Res 2007; 4: 473-8.
86. Green RC, Schneider LS, Amato DA et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease. JAMA 2009; 302: 2557-64.
87. Salloway S, Sperling R, Keren R et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011; 77: 1253-62.
88. Doody RS, Raman R, Farlow M et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013; 369: 341-50.
89. Coric V, van Dyck CH, Salloway S et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012; 69: 1-12.
90. Salloway S, Sperling R, Gilman S et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73: 2061-70.
91. European Medicines Agency. Qualification opinion of Alzheimer's disease novel methodologies/biomarkers for PET amyloid imaging (positive/negative) as a biomarker for enrichment, for use in regulatory clinical trials in predementia Alzheimer's disease. EMA/CHMP/SAWP/892998/2011. 2012.
92. European Medicines Agency. Qualification opinion of Alzheimer's disease novel methodologies/biomarkers for the use of CSF AB 1-42 and t-tau and/or PET-amyloid imaging (positive/negative) as biomarkers for enrichment, for use in regulatory clinical trials in mild and moderate Alzheimer's disease. EMA/CHMP/SAWP/893622/2011. 2012.
93. Vellas B, Andrieu S, Sampaio C, Wilcock G. Disease-modifying trials in Alzheimer's disease: a European task force consensus. Lancet Neurol 2007; 6: 56-62.
94. Vellas B, Andrieu S, Sampaio C, Coley N, Wilcock G. Endpoints for trials in Alzheimer's disease: a European task force consensus. Lancet Neurol 2008; 7: 436-50.
95. Albert MS, DeKosky ST, Dickson D et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 270-9.
96. Dubois B, Feldman HH, Jacova C et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria [see comment]. Lancet Neurol 2007; 6: 734-46.
97. Dubois B, Feldman HH, Jacova C et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol 2010; 9: 1118-27.
98. Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med 2013; 368: 1169-71.
99. Braak H, Del Tredici K. Where, when, and in what form does sporadic Alzheimer's disease begin? Curr Opin Neurol 2012; 25: 708-14.
100. Schneider LS. Prevention therapeutics of dementia. Alzheimers Dement 2008; 4: S122-30.
101. Chui H, Zheng L, Reed B, Vinters H, Mack W. Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review. Alzheimers Res Ther 2011; 4: 1.
102. Kryscio R, Abner E, Schmitt F et al. A randomized controlled Alzheimer's disease Prevention trial's evolution into an exposure trial: the Preadvise trial. J Nutr Health Aging 2013; 17: 72-5.
103. DeKosky ST, Williamson JD, Fitzpatrick AL et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008; 300: 2253-62.
104. Vellas B, Coley N, Ousset P-J et al. Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol 2012; 11: 851-9.
105. ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 2007; 68: 1800-8.
106. Peters R, Beckett N, Forette F et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol 2008; 7: 683-9.
107. Solomon A, Mangialasche F, Richard E et al. Advances in the prevention of Alzheimer's disease and dementia. J Intern Med 2014; 275: 229-250.
108. Wischik CM, Bentham P, Wischik DJ, Seng KM. O3-04-07: Tau aggregation inhibitor (TAI) therapy with Rember™ arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks. Alzheimers Dement 2008; 4: T167.
109. McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 263-9.
110. Crook T, Bartus RT, Ferris SH, Whitehouse P, Cohen GD, Gershon S. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change - report of a national institute of mental health work group. Dev Neuropsychol 1986; 2: 261-76.
111. Sperling RA, Aisen PS, Beckett LA et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 280-92.
112. 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: S13-21.
113. Galasko D, Bennett D, Sano M et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997; 11: 33-9.
114. Gelinas I, Gauthier L, McIntyre M, Gauthier S. Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther 1999; 53: 471-81.
115. Schneider LS, Olin JT, Doody RS et al. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11: S22-32.
116. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. [see comment]. Neurology 1993; 43: 2412-4.
117. DeJong R, Osterlund OW, Roy GW. Measurement of quality-of-life changes in patients with Alzheimer's disease. Clin Ther 1989; 11: 545-54.
118. Schmitt FA, Ashford W, Ernesto C et al. The Severe Impairment Battery: concurrent validity and the assessment of longitudinal change in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997; 11: S51-6.
119. Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials. Arch Neurol 2007; 64: 1323-9.
120. United States Food and Drug Administration. Guidance for industry Alzheimer's disease: developing drugs for the treatment of early stage disease (FDA-2013-D-0077) draft. US Food and Drug Administration, Center for Drug Evaluation and Research, 2013.
121. Roses AD, Welsh-Bohmer KA, Burns DK et al. A pharmacogenetics-supported clinical trial to delay onset of mild cognitive impairment due to Alzheimer's disease. J Nutr Health Aging 2012; 841: 8.
122. European Medicines Agency. Committee for medicinal products for human use. Guideline on Medicinal Products for the Treatment of Alzheimer's Disease and other Dementias CPMP/EWP/553/95 Rev. 1. 2009.
123. Leber P. Slowing the progression of Alzheimer disease: methodologic issues. Alzheimer Dis Assoc Disord 1997; 11: S10-21; discussion S37-9.
124. Holmes C, Boche D, Wilkinson D et al. Long-term effects of A[beta]42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372: 216-23.
125. Rinne JO, Brooks DJ, Rossor MN et al. 11C-PiB PET assessment of change in fibrillar amyloid-[beta] load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 2010; 9: 363-72.
126. Blennow K, Zetterberg H, Rinne JO et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 2012; 69: 1002-10.
127. Gauthier S, Aisen P, Ferris S et al. Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the alphase study. J Nutr Health Aging 2009; 13: 550-7.
128. Sköldunger A, Johnell K, Winblad B, Wimo A. Mortality and treatment costs have a great impact on the cost-effectiveness of disease modifying treatment in Alzheimer's disease - A simulation study. Curr Alzheimer Res 2013; 10: 207-16.
129. European Medicines Agency. Qualification opinion of a novel data driven model of disease progression and trial evaluation in mild and moderate Alzheimer's disease. EMA/CHMP/SAWP/420174/2013, 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2013/07/WC500146179.pdf.
130. Leber P. Not in our methods, but in our ignorance.[comment]. Arch Gen Psychiatry 2002; 59: 279-80.
131. Frolich L, Ashwood T, Nilsson J, Eckerwall G. Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. J Alzheimers Dis 2010; 24: 363-74.
132. Hilt D, Gawryl M, Koenig G et al. Positive effects on cognition and clinical function in mild to moderate Alzheimer's disease patients with a selective alpha-7 nicotinic partial agonists: interpretation of effects based on a PK/PD model. 5th Conference Clinical Trials on Alzheimer's Disease. Monte Carlo:J Nutr Health Aging 2012; 819: 25.
133. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. [update of Cochrane Database Syst Rev. 2005;(3):CD003154; PMID: 16034889]. Cochrane Database Syst Rev 2006; 2: CD003154.
134. Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011; 68: 991-8.
135. Schneider L. Pharmacological Treatment of Alzheimer's Disease. In: Hampel HCM, ed. Alzheimer's Disease - Modernizing Concept, Biological Diagnosis and Therapy. Basel: Karger, 2012; 122-67.
136. Geldmacher DS, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 2011; 68: 45-50.
137. Vellas B, Sol O, Snyder PJ et al. EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 2011; 8: 203-12.
138. Aisen PS, Gauthier S, Ferris SH et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 2011; 7: 102-11.
139. Lannfelt L, Blennow K, Zetterberg H et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβετα as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008; 7: 779-86.
140. Winblad B, Andreasen N, Minthon L et al. Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012; 11: 597-604.
141. Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME(R) technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin 2010; 6: 948-52.
142. Scheltens P, Sperling R, Salloway S, Fox N. Bapineuzumab IV phase 3 results. 5th Conference Clinical Trials on Alzheimer's Disease. Monte Carlo: J Nutr Health Aging 2012; 797: 3.
143. Doody R. Safety and efficacy of solanezumab in patient with mild to moderate Alzheimer's disease: results from phase 3. 5th Conference Clinical Trials on Alzheimer's Disease. Monte Carlo: J Nutr Health Aging 2012; 16: 801-2.
144. Ostrowitzki S, Deptula D, Thurfjell L et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2011; 69: 198-207. archneurol.2011.1538.
145. Dodel R, Neff F, Noelker C et al. Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence. Drugs 2010; 70: 513-28.
146. Dodel R, Rominger A, Bartenstein P et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 2013; 12: 233-43.
147. Baxter. Baxter announces topline results of phase 3 study of immunoglobulin for Alzheimer's disease. Deerfield. 2013.
148. Hampel H, Ewers M, Berger K, Annas P. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009; 70: 922-31.
149. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011; 198: 351-6.
150. Tariot PN, Schneider LS, Cummings J et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011; 68: 853-61.
151. del Ser T, Steinwachs KC, Gertz HJ et al. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis 2012; 33: 205-15.
152. TauRX T. First UK patients enroll in Phase 3 clinical trials of LMTX™ for Alzheimer's Disease (press release). 2013.
153. Wischik DJ. Disease-modifying power estimation for TauRx global phase 3 trial program in AD with tau-aggregation inhibitor LMTX. 5th Conference Clinical Trials on Alzheimer's Disease. Monte Carlo: J Nutr Health Aging 2012; 824: 30.
154. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol 2006; 63: 1402-8.
155. Freund-Levi Y, Hjorth E, Lindberg C et al. Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease: the OmegAD study. Dement Geriatr Cogn Disord 2009; 27: 481-90.
156. Arai H, Takahashi T. A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease: pilot follow-up study. Am J Geriatr Psychiatry 2009; 17: 353-4.
157. Craft S, Baker LD, Montine TJ et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69(1): 29-38. doi:10.1001/archneurol.2011.233.