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Alzheimer's disease failed clinical trials
Abstract
Alzheimer's disease is a progressive neurodegenerative disease typically presenting with symptoms of memory loss and cognitive decline. Existing theories for the causation of this focuses on amyloid beta plaques and neurofibrillary tau tangles. Most US Food and Drug Administration approved therapies for Alzheimer's disease target cognitive function. A multitude of clinical trials, with a variety of different targets have been conducted over the decades which have focused on the two clinical signs, with the only success being the controversial 2021 approval of an IgG1 anti-Ab antibody targeting the clearance of the Aβ plaques. Presented is a review of all previously failed Alzheimer's disease clinical trials and the rationale for their failures.
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“Second-generation anti-amyloid antibody against soluble monomeric Aβ (solanezumab), insoluble monomeric Aβ (gantenezumab), and monoclonal antibody against multiple Aβ forms (crenezumab) failed to have efficacy in improving cognitive functions for mild and moderate AD in several clinical trials (Table 2, for example [36]).”
From Current therapeutics for Alzheimer’s disease and clinical trials (2024) · cites this paper as [36]
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Cites
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016) · Nature · doi:10.1038/nature19323 · Cited by 3,059
2020 Alzheimer's disease facts and figures
(2020) · Alzheimer's & Dementia · doi:10.1002/alz.12068 · Cited by 2,353
The cholinergic hypothesis of Alzheimer’s disease: A review of progress
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.66.2.137 · Cited by 2,198
Amyloid Precursor Protein Processing and Alzheimer's Disease
O'Brien, R. J., & Wong, P. C. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113613 · Cited by 2,061
Alzheimer's Disease and the Amyloid-β Peptide
Murphy, M. P., & LeVine, H. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1221 · Cited by 1,750
Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures
Cummings, J. L., Morstorf, T., & Zhong, K. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt269 · Cited by 1,744
A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
Doody, R. S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1210951 · Cited by 1,224
Alzheimer's disease drug development pipeline: 2019
Cummings, J., Lee, G., Ritter, A., Sabbagh, M., & Zhong, K. (2019) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.05.008 · Cited by 762
The Episodic Memory System: Neurocircuitry and Disorders
Dickerson, B. C., & Eichenbaum, H. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.126 · Cited by 740
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723
Risner, M. E., Saunders, A. M., Altman, J. F. B., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., Roses, A. D., & for the Rosiglitazone in Alzheimer's Disease Study Group (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500369 · Cited by 686
NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18162 · Cited by 634
Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis
Viola, K. L., & Klein, W. L. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1386-3 · Cited by 628
Watson, G. S., Cholerton, B. A., Reger, M. A., Baker, L. D., Plymate, S. R., Asthana, S., Fishel, M. A., Kulstad, J. J., Green, P. S., Cook, D. G., et al. (2005) · American Journal of Geriatric Psychiatry · doi:10.1176/appi.ajgp.13.11.950 · Cited by 614
The Alzheimer's disease Beta-secretase enzyme, BACE1
Cole, S. L., & Vassar, R. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-22 · Cited by 550
Randomized trial of verubecestat for prodromal Alzheimer's disease
Egan, M. F., Kost, J., Voss, T., Mukai, Y., Aisen, P. S., Cummings, J. L., Tariot, P. N., Vellas, B., van Dyck, C. H., Boada, M., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1812840 · Cited by 545
Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation In Vivo
Noble, W. J., Olm, V., Takata, K., Casey, E., Mary, O., Meyerson, J. L., Gaynor, K., LaFrancois, J. J., Wang, L., Kondo, T., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00259-9 · Cited by 511
The mechanism of γ‐Secretase dysfunction in familial Alzheimer disease
Chávez‐Gutiérrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.79 · Cited by 495
Clinical uses of intravenous immunoglobulin
Jolles, S. R. A., Sewell, W. A. C., & Misbah, S. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02834.x · Cited by 374
Coric, V., van Dyck, C. H., Salloway, S., Andreasen, N., Brody, M., RICHTER, R. W., Soininen, H. S., Thein, S., Shiovitz, T. M., Pilcher, G. D., et al. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.2194 · Cited by 374
Gold, M., Alderton, C., Zvartau-Hind, M., Egginton, S., Saunders, A. M., Irizarry, M., Craft, S., Landreth, G., Linnamägi, Ü., & Sawchak, S. (2010) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000318845 · Cited by 361
Mandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5268-11.2012 · Cited by 355
May, P. C., Dean, R. A., Lowe, S. L., Martenyi, F., Sheehan, S. M., Boggs, L. N., Monk, S. A., Mathes, B. M., Mergott, D. J., Watson, B. M., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3647-11.2011 · Cited by 336
Fleisher, A., Raman, R., Siemers, E., Becerra, L. M., Clark, C. M., Dean, R. A., Farlow, M. R., Galvin, J. E., Peskind, E. R., Quinn, J. F., et al. (2008) · Archives of Neurology · doi:10.1001/archneur.65.8.1031 · Cited by 332
Brioni, J. D., Esbenshade, T. A., Garrison, T. R., Bitner, S. R., & Cowart, M. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.166876 · Cited by 331
Yiannopoulou, K. G., Anastasiou, A. I., Zachariou, V., & Pelidou, S.-H. (2019) · Biomedicines · doi:10.3390/biomedicines7040097 · Cited by 330
Yamanaka, M., Ishikawa, T., Griep, A., Axt, D., Kummer, M. P., & Heneka, M. T. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1569-12.2012 · Cited by 326
Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis
Gervais, F., Paquette, J., Morissette, C., Krzywkowski, P., Yu, M. W. N., Azzi, M., Lacombe, D., Kong, X., Aman, A. M., Laurin, J., et al. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.02.015 · Cited by 313
18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease
Relkin, N. R., Szabo, P., Adamiak, B., Burgut, T., Monthé, C., Lent, R. W., Younkin, S. G., Younkin, L. H., Schiff, R. I., & Weksler, M. E. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.12.021 · Cited by 305
Role of RAGE in Alzheimer’s Disease
Cai, Z., Liu, N., Wang, C., Qin, B., Zhou, Y., Xiao, M., Chang, L., Yan, L., & Zhao, B. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0233-3 · Cited by 295
Aisen, P. S., Gauthier, S., Ferris, S. H., Saumier, D., Haine, D., Garceau, D., Duong, A., Suhy, J., Oh, J., Lau, W. C., et al. (2011) · Archives of Medical Science · doi:10.5114/aoms.2011.20612 · Cited by 295
Wilcock, G. K., Black, S. E., Hendrix, S. B., Zavitz, K. H., Swabb, E. A., & Laughlin, M. A. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70090-5 · Cited by 291
Developing β‐secretase inhibitors for treatment of Alzheimer’s disease
Ghosh, A. K., Brindisi, M., & Tang, J. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07476.x · Cited by 282
A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease
Salloway, S., Sperling, R., Keren, R., Porsteinsson, A. P., van Dyck, C. H., Tariot, P. N., Gilman, S., Arnold, D., Abushakra, S., Hernandez, C., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e3182309fa5 · Cited by 258
Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective
Dunn, B., Stein, P., & Cavazzoni, P. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2021.4607 · Cited by 246
Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease
TCW, J., & Goate, A. M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024539 · Cited by 242
Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial
Coric, V., Salloway, S., van Dyck, C. H., Dubois, B., Andreasen, N., Brody, M., Curtis, C., Soininen, H., Thein, S., Shiovitz, T., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0607 · Cited by 240
Hongpaisan, J., Sun, M., & Alkon, D. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5209-10.2011 · Cited by 231
Neurofibrillary Tangles and Alzheimer’s Disease
Brion, J. (1998) · European Neurology · doi:10.1159/000007969 · Cited by 208
A Phase II study targeting amyloid-β with 3APS in mild-to-moderate Alzheimer disease
Aisen, P. S. S., Saumier, D., Briand, R., Laurin, J., Gervais, F., Tremblay, P., & Garceau, D. (2006) · Neurology · doi:10.1212/01.wnl.0000244346.08950.64 · Cited by 198
Harrington, C. M., Sawchak, S. T., Chiang, C., Davies, J., Donovan, C., Saunders, A. M., Irizarry, M. C., Jeter, B., Zvartau-Hind, M. E., van Dyck, C. H., et al. (2011) · Current Alzheimer Research · doi:10.2174/156720511796391935 · Cited by 198
Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease
Galasko, D. R., Bell, J. S., Mancuso, J. Y., Kupiec, J. W., Sabbagh, M. N., van Dyck, C. H., Thomas, R. G., Aisen, P. S. S., & Study, F. T. A. D. C. (2014) · Neurology · doi:10.1212/wnl.0000000000000364 · Cited by 190
Sabbagh, M. N., Agro, A., Bell, J. S., Aisen, P. S. S., Schweizer, E. E., & Galasko, D. R. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318204b550 · Cited by 164
A phase 3 trial of IV immunoglobulin for Alzheimer disease
Relkin, N. R., Thomas, R. G., Rissman, R. A., Brewer, J. B., Rafii, M. S., van Dyck, C. H., Jack, C. R., Sano, M., Knopman, D. S., Raman, R., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000003904 · Cited by 157
β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease
Menting, K. W., & Claassen, J. A. H. R. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00165 · Cited by 144
Properties of scyllo–inositol as a therapeutic treatment of AD-like pathology
Fenili, D., Brown, M., Rappaport, R. V., & McLaurin, J. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0156-7 · Cited by 136
Lahiri, D. K., Chen, D., Maloney, B., Holloway, H. W., Yu, Q.-S., Utsuki, T., Giordano, T., Sambamurti, K., & Greig, N. H. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.112102 · Cited by 134
BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease
Maia, M., & Sousa, E. (2019) · Pharmaceuticals · doi:10.3390/ph12010041 · Cited by 134
Dodel, R. C., Balakrishnan, K., Keyvani, K., Deuster, O., Neff, F., Andrei‐Selmer, L., Röskam, S., Stüer, C., Al‐Abed, Y., Noelker, C., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4401-10.2011 · Cited by 129
Galasko, D. R., Graff‐Radford, N. R., May, S. J., Hendrix, S. B., Cottrell, B. A., Sagi, S. A., MATHER, G. G., Laughlin, M. A., Zavitz, K. H., Swabb, E. A., et al. (2007) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31815d1048 · Cited by 122
Maccecchini, M. L., Chang, M. Y., Pan, C., John, V., Zetterberg, H., & Greig, N. H. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-302589 · Cited by 98
Farlow, M. R., Thompson, R. E., Wei, L., Tuchman, A. J., Grenier, E., Crockford, D., Wilke, S., Benison, J., & Alkon, D. L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180759 · Cited by 85
Vohora, D., & Bhowmik, M. (2012) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2012.00072 · Cited by 75
Intravenous immunoglobulin and Alzheimer’s disease: what now?
Loeffler, D. A. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-70 · Cited by 52
LRP in Alzheimer’s disease: friend or foe?
Ulery, P. G., & Strickland, D. K. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11455 · Cited by 42
Portelius, E., Dean, R. A., Andréasson, U., Mattsson, N., Westerlund, A., Olsson, M., Demattos, R. B., Racke, M. M., Zetterberg, H., May, P. C., et al. (2014) · Alzheimer s Research & Therapy · doi:10.1186/s13195-014-0075-0 · Cited by 38
Inhibition of γ-Secretase Leads to an Increase in Presenilin-1
Sogorb‐Esteve, A., García‐Ayllón, M., Llansola, M., Felipo, V., Blennow, K., & Sáez‐Valero, J. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0705-1 · Cited by 27
Amino Acid Sequence and Structural Comparison of BACE1 and BACE2 Using Evolutionary Trace Method
Mirsafian, H., Ripen, A. M., Merican, A. F., & Mohamad, S. B. (2014) · The Scientific World JOURNAL · doi:10.1155/2014/482463 · Cited by 23
Acetylcholinesterase Inhibitors for Alzheimer’s disease: Past, Present, and Potential Future
Truong, B., Quiroz, J. A., & Priefer, R. (2020) · Medical Research Archives · doi:10.18103/mra.v8i12.2271 · Cited by 10
Self-citationTramiprosate (Alzhemed) for Alzheimer's disease
Malouf, R. S., & Collins, H. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007549.pub2 · Cited by 3
Research works printed but not linked: 1
- Schindowski, 2014, Intravenous immunoglobulin for the treatment of Alzheimer's disease: current evidence and considerations, Degener. Neurol. Neuromuscul. Dis., 4, 121
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Metadata
- Authors
- Asher, S., & Priefer, R.
- Affiliations
- Massachusetts College of Pharmacy and Health Sciences (US)
- Corresponding author
- Priefer, Ronny
- ORCID
- Priefer, Ronny
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 306
- Pages
- 120861
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W4289732088
- Cited by
- 124
- References
- 61
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 34 · 2023: 29 · 2022: 8
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, clinical trial failure, amyloid plaques, tau tangles, anti-amyloid therapy, anti-tau therapy, cognitive function, neurodegeneration, therapeutic target
- MeSH terms
- Alzheimer Disease, Clinical Trials as Topic, Humans, Amyloid beta-Peptides, Plaque, Amyloid
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