Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease
Open accessAbstract
BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.
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About 40% of patients treated with aducanumab experienced life-threatening side effects, including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H).
“about 40% of patients treated with the mab aducanumab experienced life-threatening side effects, including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H)”
From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Budd Haeberlein et al. 2022
The Safety section identifies ARIA-E and ARIA-H as adverse events, but it does not characterize roughly 40% of treated patients as having life-threatening effects. It reports serious ARIA events in only 1.5% and 1.4% of the high-dose groups, says a minority of participants with ARIA had symptoms, and reports no fatal ARIA events. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAnti-amyloid antibodies can clear Aβ plaques from the brain, leading to a slowing of cognitive and functional decline in individuals with MCI and mild dementia due to AD.
“Several phase 3 trials demonstrated that anti-amyloid antibodies can clear Aβ plaques from the brain6–8, which leads to a slowing of cognitive and functional decline in individuals with mild cognitive impairment (MCI) and mild dementia due to AD.”
From Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests (2024) · cites this paper as [6]
The Efficacy section reports dose- and time-dependent reductions in brain amyloid PET measures in both phase 3 trials, which enrolled people with MCI or mild dementia due to AD. The Discussion reports slower clinical decline in EMERGE but says ENGAGE did not meet its clinical endpoints; it describes plaque removal as possibly associated with clinical benefit, not as establishing that plaque clearance leads to slower decline. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnti-Aβ immunotherapies have shown reductions in amyloid PET, and several amyloid reducing therapies for AD use amyloid PET (or CSF) as a key endpoint.
“Anti-Aβ immunotherapies have shown reductions in amyloid PET and several amyloid reducing therapies for AD use amyloid PET (or CSF) as a key endpoint [172, 173].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [172]
The Efficacy section reports dose- and time-dependent reductions in amyloid PET signal with aducanumab in both EMERGE and ENGAGE. The Statistical analyses section says amyloid PET was the only biomarker outcome with a sample-size calculation, but all biomarker analyses were exploratory. This paper does not establish that several different amyloid-reducing therapies use PET or CSF as key endpoints. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAnti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab have demonstrated robust amyloid clearance with statistically significant but modest clinical effects.
“Three anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab have demonstrated robust amyloid clearance, with statistically significant but modest clinical effects”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [10]
The Efficacy section reports substantial amyloid PET reductions with aducanumab, and the Discussion reports statistically significant slowing of clinical decline in the high-dose EMERGE arm. But the Discussion also says ENGAGE did not meet its clinical endpoints. The Introduction describes robust amyloid reduction with newer anti-amyloid antibodies, but this paper does not establish statistically significant clinical effects for lecanemab and donanemab. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhase 2 and phase 3 trials of aducanumab, lecanemab, donanemab, and gantenerumab targeting Aβ required PET or CSF evidence of amyloid pathology for trial enrolment.
“Phase 2 and phase 3 trials of the monoclonal antibodies -- aducanumab, lecanemab, and donanemab, as well as the discontinued gantenerumab -that target Aβ plaques, fibrils, soluble protofibrils, and oligomeric Aβ species all required PET or CSF evidence of amyloid pathology for trial enrolment. (460-463)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [461]
In two conflicting, identically designed phase 3 trials, aducanumab was associated with less decline than placebo of 0.39 (0.09-0.69) CDR-SB points at 18 months in one study, and a statistically non-significant outcome favouring placebo in the other.
“In two conflicting, identically designed phase 3 trials, aducanumab was associated with less decline than placebo of 0.39 (0.09-0.69) Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) points (out of a total possible score of 18) at 18 months in one study, and a statistically non-significant outcome favouring placebo in the other. (461)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [461]
Aducanumab finished two large Phase III clinical trials, with dose- and time-dependent reduction in AD pathology observed in both trials.
“Based on encouraging initial results,527 aducanumab, an antibody for Aβ, recently finished two large Phase III clinical trials. A dose- and time-dependent reduction in the pathology of AD was observed in both trials.528”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [528]
Amyloid-lowering biologics reduce plaque burden but their clinical efficacy remains limited.
“Although amyloid-lowering biologics reduce plaque burden, their clinical efficacy remains limited, and concerns such as amyloid-related imaging abnormalities (ARIA), restricted patient eligibility, and high treatment burden underscore the need for alternative strategies that restore neural function through regenerative mechanisms.”
From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [6]
In LMICs, dementia is often not recognised and diagnosed, and when it is, people living with dementia often face a lack of resources for treatment and care, including treatment of other illnesses and support for families.
“In LMICs, dementia is often not recognised and diagnosed and, when it is, people living with dementia are often faced with a lack of resources for treatment and care, including treatment of other illnesses and support for families. (471)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [471]
The Clinical study patients and Discussion passages describe aducanumab trial participants and the limits of generalizing the trial results, not dementia recognition or care in LMICs. Searches for LMIC diagnosis, treatment resources, other illnesses, and family support found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredInfusion-related reactions occur in about 26% of patients on lecanemab and 7.4% of patients on placebo.
“infusion-related reactions, in about 26% of patients on lecanemab, and only 7.4% of patients on placebo. (507) (460, 461)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [461]
The Safety and Discussion passages report adverse events in the aducanumab EMERGE and ENGAGE trials, not infusion-related reactions in lecanemab recipients. Searches for lecanemab, infusion-related reactions, and the stated percentages found no passage addressing the claimed 26% versus 7.4% rates; page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Budd Haeberlein, S., Aisen, P. S., Barkhof, F., Chalkias, S., Chen, T., Cohen, S., Dent, G., Hansson, O., Harrison, K., von Hehn, C., Iwatsubo, T., Mallinckrodt, C., Mummery, C. J., Muralidharan, K. K., Nestorov, I., Nisenbaum, L., Rajagovindan, R., Skordos, L., Tian, Y., van Dyck, C. H., Vellas, B., Wu, S., Zhu, Y., & Sandrock, A.
- Affiliations
- University of Southern California (US)
- Amsterdam University Medical Centers (NL)
- Biogen (United States) (US)
- Lund University (SE)
- The University of Tokyo (JP)
- UCL Queen Square Institute of Neurology (GB)
- Université Toulouse III - Paul Sabatier (FR)
- ORCID
- Venue
- The Journal of Prevention of Alzheimer's Disease
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 9
- Issue
- 2
- Pages
- 197-210
- ISSN
- 2274-5807 (ISSN-L)
- OpenAlex
- W4225741213
- Cited by
- 1,367
- References
- 9
- Citations by year
- 2026: 238 · 2025: 395 · 2024: 393 · 2023: 276 · 2022: 64 · 2012: 1
- FWCI
- 174.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Pure Amsterdam UMC (acceptedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Foundation for the National Institutes of Health
- Alzheimer's Association
- Eli Lilly and Company
- Pfizer
- Biogen
- Moderna
- National Institute for Health and Care Research
- Eisai
- Université de Toulouse
- University College London Hospitals NHS Foundation Trust
- IXICO
- National Institutes of Health
- Genentech
- Avid Radiopharmaceuticals
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- aducanumab, Alzheimer's disease, early Alzheimer's disease, amyloid-beta, anti-amyloid monoclonal antibodies, mild cognitive impairment, mild dementia, CDR-SB, amyloid-related imaging abnormalities, target engagement, amyloid PET, futility analysis, drug safety, dose-response relationship, disease biomarkers
- MeSH terms
- Alzheimer Disease, Humans, Biomarkers, Amyloid beta-Peptides, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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