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Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019
Open accessAbstract
Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.
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“Furthermore, studies such as those by Salloway et al. and Biogen’s EMERGE and ENGAGE trials found that treating the plaques alone did not rescue cognitive defects (Knopman et al., 2021; Salloway et al., 2014).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Knopman et al., 2021
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“however, thus far, treatments to decrease formation of plaques have shown only minimal or no improvement in disease progression or outcomes (Knopman et al., 2021; Selkoe, 2019).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Knopman et al., 2021
In the citing paper
“The FDA has controversially granted accelerated approval to aducanumab and has opined that the reduction of amyloid is reasonably likely to predict clinical benefit 7,9,[98][99][100][101][102][103][104][105][106][107] .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [7]
In the citing paper
“In spite of this, the FDA granted expedited approval on the grounds of the EMERGE trial’s documented decrease in amyloid levels [132,185,186,187].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
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“Aducanumab demonstrated inconsistent outcomes in its two main clinical trials, the Phase III EMERGE and ENGAGE research investigations.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
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“In the EMERGE experiment, when participants with AD were at risk for cognitive deterioration, there was a decrease in the amount of amyloid-beta plaques.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
In the citing paper
“However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.348,349”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [348]
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“…inhibitors (AChEI), N-methyl-D-aspartate (NMDA) receptor antagonists (Li et al., 2015) and recently approved anti-amyloid antibody therapies with aducanumab (Ferrero et al., 2016; Sevigny et al., 2016; Knopman et al., 2021; Tolar et al., 2020) and lecanemab (van Dyck et al., 2023).”
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Biography as the dark matter of treatment response
Horwitz, R. I., Conroy, A. H., Cullen, M. R., & Sim, I. (2026) · The American Journal of Medicine · doi:10.1016/j.amjmed.2026.01.044 · Cited by 2
Lu, C.-W., Ng, T.-C., Cheng, Y.-C., & Su, C.-H. (2026) · Healthcare · doi:10.3390/healthcare14050689 · Cited by 2
Krüger, K., van der Veen, H., Beigy, M., O’Donovan, S. D., van Riel, N. A. W., Remie, L. B., Aarts, E., Steegenga, W. T., Smeets, P. A. M., van Trijp, M. P. H., et al. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1738622 · Cited by 3
Yao, M., Liu, A., Song, J., Xing, L., Zi, M., & Li, H. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.06.001 · Cited by 2
Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease
Shvetcov, A., Thomson, S., Graham, M. E., Hauger, B. M., Keller, J. E., Smoyer, C. J., Tague, S. E., Cho, A., Imam, F. B., Krish, V. S., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71714 · Cited by 6
Development of Monoclonal Antibody Therapeutics for Alzheimer's Disease
Takeda, M. (2022) · Taiwanese Journal of Psychiatry · doi:10.4103/tpsy.tpsy_31_22 · Cited by 2
Zarrilli, B., Bonanni, R., Belfiore, M., Severino, M., Cariati, I., Fioravanti, R., Cappella, G., Sennato, S., Frank, C., Giordani, C., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-77859-9 · Cited by 3
“Unfortunately, there is a lot of concern and prudence about the real clinical efficacy of this drug and on secondary effects 23 and it has been withdran from the market in 2024.”
Alzheimer's disease: part 2 – the present
Nitríni, R. (2024) · Arquivos de Neuro-Psiquiatria · doi:10.1055/s-0044-1791755 · Cited by 3
“62,63 Aducanumab treatment produced statistically signi fi cant, dose-dependent reductions in CSF p-Tau levels, CSF total-Tau levels, and in brain amyloid plaque versus placebo, as measured by PET, at week 78.”
Exploring Abeta42 monomer diffusion dynamics on fibril surfaces through molecular simulations
Ma, Y., Wang, G., Chen, H., & Tsai, M. (2025) · Protein Science · doi:10.1002/pro.70131 · Cited by 2
Pro-cognitive efficacy of Prospekta in a rat model of age-associated cognitive impairment
Kardash, E., Petrova, N., Ganina, K., Тарасов, С. А., & Epstein, O. I. (2025) · BMC Neuroscience · doi:10.1186/s12868-025-00958-4 · Cited by 3
“Aducanumab and lecanemab are FDA-approved monoclonal antibodies that target the pathophysiological mechanisms of Alzheimer’s disease and slow the disease process [7], yet their efficacy and safety profiles are being questioned, especially in older patients [8, 9].”
Kim, H., Yoo, S., Kwak, H., Ma, S., Kim, R., Lee, M., Ha, N., Pyo, S., Kwon, S.-G., Cho, E.-H., et al. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01813-8 · Cited by 9
“However, the limited efficacy in improving cognitive function is likely due to continued synapse loss even after Aβ clearance [15, 16, 17, 18].”
Cong, B., Xie, H., Sun, Y., Ni, J., Shi, J., Wei, M., Li, F., Wang, H., Wang, L., Qin, B., et al. (2025) · Frontiers of Medicine · doi:10.1007/s11684-025-1154-2 · Cited by 2
Aducanumab Fails to Produce Efficacy Results Yet Obtains US Food and Drug Administration Approval
Angelo, M., & Ward, L. (2021) · Population Health Management · doi:10.1089/pop.2021.0189 · Cited by 2
Pharmacotherapy for Alzheimer’s disease: what’s new on the horizon?
Khoury, R., Gallop, A., Roberts, K., Grysman, N., Lu, J., & Grossberg, G. T. (2022) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2022.2097868 · Cited by 2
“between biomarker changes and cognition has not been well established with this compound [123].”
BackgroundDib, M., Ampil, E. R., Kee, H. F., Krespi, Y., Mahdawi, A. M. A., Ogun, S. A., Pakdaman, H., & Rejdak, K. (2022) · Journal of Neurology Research Review & Reports · doi:10.47363/jnrrr/2022(4)160 · Cited by 1
Inoue, M., Kimoto, K., Honma, Y., Tomita, R., & Manabe, Y. (2022) · Psychogeriatrics · doi:10.1111/psyg.12899 · Cited by 2
Pakdaman, H., Harandi, A. A., Gharagozli, K., Siavoshi, F., Barough, S. S., Sharifipour, E., Esfandani, A., Ilkhani, S., Tabatabaei, F., & Sobhanian, S. A. (2023) · Current Aging Science · doi:10.2174/1874609816666230224111759 · Cited by 2
A protein aggregation platform that distinguishes oligomers from amyloid fibrils
Zhang, A., Barron, D. P., Chen, E. W., & Guo, Z. (2023) · The Analyst · doi:10.1039/d3an00487b · Cited by 2
Industry News Update Covering June 2021
SIMPSON, I. A. (2021) · Therapeutic Delivery · doi:10.4155/tde-2021-0063 · Cited by 2
Longitudinal analysis of the gut microbiome in the 5xfAD mouse model of Alzheimer’s diseasePreprint
Dunham, S. J. B., McNair, K. A., Adams, E. D., Avelar‐Barragan, J., Forner, S., Mapstone, M. E., & Whiteson, K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.02.482725 · Cited by 2
Biel, D., Suárez‐Calvet, M., Hager, P., Rubinski, A., Dewenter, A., Steward, A., Roemer, S. N., Ewers, M., Haass, C., Brendel, M., et al. (2022) · medRxiv · doi:10.1101/2022.08.26.22279269 · Cited by 2
“trials focusing on the reduction of Ab plaques have failed to significantly reduce cognitive dysfunction (55).”
BackgroundLee, J., Lee, K., Kim, M. S., Kim, M. W., Lim, M., Yoo, J., & Lee, S. H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.19.563032 · Cited by 2
Twenty-five years of novel drug approvals in rheumatology
Henry, K. A., Anumolu, N., & Putman, M. (2023) · Lara D. Veeken · doi:10.1093/rheumatology/kead335 · Cited by 1
Application of a Novel Endpoint Staging Framework: Proof of Concept in the AMBAR Study
Podger, L., Stewart, W. F., Serrano, D., Lipton, R. B., Gómez‐Ulloa, D., Ayasse, N. D., Barnes, F. B., Davis, E. A., & Runken, M. C. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231197 · Cited by 1
“Efforts to develop a disease-modifying therapy (DMT) for AD have been largely unsuccessful; two DMTs (aducanumab and lecanemab) have been granted accelerated approval to date, with the clinical benefit of aducanumab yet to be confirmed in the upcoming confirmatory trial(s) [4].”
BackgroundAmplifying Efficiency and Accuracy in Dementia Drug Development
Lerch, O., Levine, S. Z., Sivakumaran, S., Lutz, M. W., Chiba‐Falek, O., Mazer, N. A., Bairu, M., Haraldsen, I., Rossini, P. M., Snyder, P. J., et al. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.167 · Cited by 1
“Medicare’s restricted coverage to clinical trials further limited its use, ultimately leading to its commercial failure (9, 10).”
NGF-based cholinergic therapies in Alzheimer disease
Mitra, S., Gera, R., & Eriksdotter, M. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19088-9.00007-x · Cited by 1
Exploring prodrug approaches for Alzheimer’s treatment: an overview
Kumari, P., Kumar, D., Chopade, S. S., & Karati, D. (2025) · Neurodegenerative Disease Management · doi:10.1080/17582024.2025.2514990 · Cited by 1
de Souza, F. N., de Oliveira, N. K. S., de Lima, H. B., Silva, A. G., Cruz, R. A. S., de Oliveira, F. R., Federico, L. B., & Hage-Melim, L. I. D. S. (2025) · Applied Sciences · doi:10.3390/app151910340 · Cited by 1
Goonetilleke, U. K. D. A. (2025) · Springer eBooks · doi:10.1007/978-981-96-0523-1_35 · Cited by 1
Analysis of the dual role of amyloid-beta in Alzheimer’s disease through multi-omics integration
Guo, J., Lu, X., Qiu, L., Xue, W., Fu, H., Wang, K., & Wang, Y. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00872 · Cited by 2
da Silva, A. M. P., de Deus, O., Cardoso, L. J. C., Ribeiro, F. V., Meldola, P. F., Menezes, I. R., Han, M. L., Quiroga, D. G., Almeida, K. J., Santos, D. H., et al. (2026) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2026.2631536 · Cited by 1
“The cognitive benefits are of marginal magnitude, and their long-term impact on disease progression remains uncertain [9,10,22,24,49,50].”
Mayeri, Z., Woods, G., Rane, A., Kifle, A., Chamoli, M., Shukla, S., Walton, C. C., & Andersen, J. K. (2026) · GeroScience · doi:10.1007/s11357-026-02139-5 · Cited by 2
Hussain, Z., Ng, D., Leighton, S., Deligianni, F., Ritchie, C. W., & Cavanagh, J. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71257 · Cited by 1
“5,6 Beyond anti-amyloid therapies, several inflammatory pathways havebeenevaluatedastherapeutictargetsinAD,includinginterleukin (IL)-1 β blockade, tumor necrosis factor alpha (TNF-α ) inhibitors, NOD-like receptor protein 3 (NLRP3)-inflammasome inhibitors, and IL-17A pathway modulation.”
Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer’s disease therapy
Ouro, A., Ben-Dor, G. A., Debasa‐Mouce, M., Gulkarov, S., Leon, J. D., Castro‐Mosquera, M., Sobrino, T., Bougea, A. M., & Reiss, A. B. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1766762 · Cited by 1
“In both the EMERGE and ENGAGE trials, amyloid PET imaging showed dose-related reductions in brain A β , indicating target engagement (Knopman et al., 2020).”
Coles, M., Porto, R. R., Chesworth, R., Steiner-Lim, G. Z., & Karl, T. (2026) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2026.04.003 · Cited by 2
Hoang, M. T., Kahn, J. G., Saha, S., & Trépel, D. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71308 · Cited by 3
Metadata
- Authors
- Knopman, D. S., Jones, D. T., & Greicius, M. D.
- Affiliations
- Mayo Clinic (US)
- Stanford Medicine (US)
- Corresponding author
- Knopman, David S.
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-11
- Volume
- 17
- Issue
- 4
- Pages
- 696-701
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W3097527510
- Cited by
- 524
- References
- 13
- Citations by year
- 2026: 53 · 2025: 55 · 2024: 75 · 2023: 107 · 2022: 151 · 2021: 79 · 2020: 4
- FWCI
- 51.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- 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
- aducanumab, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amyloid, Dose-Response Relationship, Drug, Humans, Biomarkers, Treatment Outcome, Treatment Failure, Clinical Trials, Phase III as Topic, Antibodies, Monoclonal, Humanized
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