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Trial of solanezumab in preclinical Alzheimer's disease
Open accessAbstract
Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer’s disease have had mixed results. Download a PDF of the Research Summary. We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer’s disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini–Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was −1.43 in the solanezumab group and −1.13 in the placebo group (difference, −0.30; 95% confidence interval, −0.82 to 0.22; P=0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer’s disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.) QUICK TAKE VIDEO SUMMARYSolanezumab in Preclinical Alzheimer’s Disease 02:05
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“Similarly a trial of solanezumab did not slow cognitive decline in people with pre-clinical Alzheimer's disease , did not affect amyloid plaque level but influenced CDR-SB in line with the other studies (0.34). (498) (497)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [498]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“approximately 30% of participants in either group progressed to symptomatic AD (stage 3 or stage 4 of AD).”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [14]
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“The A4 (Anti-Amyloid treatment in Asymptomatic Alzheimer’s disease) study, a 5-year clinical trial examining the effects of solanezumab in asymptomatic individuals with amyloid accumulation, failed to show significant cognitive benefits.14”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [14]
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“Most importantly, the participants who eventually progressed, in fact, had higher levels of accumulated Aβ42 levels measured in post-treatment PET.”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“While recent clinical trials of anti‐amyloid therapies, such as donanemab and lecanemab, 2 , 3 have shown promising results, the failures of earlier treatments like solanezumab and bapineuzumab indicate that targeting a single AD‐specific pathological process is insufficient to mitigate cognitive decline. 4 , 5 , 6”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [4]
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“In a more recent phase 3 trial (NCT02008357), solanezumab failed to meet primary and secondary outcomes, as the drug did not slow cognitive decline in preclinical AD or reduce the risk of progression to symptomatic AD [80].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [80]
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“Despite a well-defined study population and an extended treatment period, results indicated no substantial difference in cognitive decline between the treatment and placebo groups.”
From A 2025 update on treatment strategies for the Alzheimer’s disease spectrum (2025) · cites this paper as [14]
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“The A4 study was designed to test whether solanezumab could slow cognitive decline by targeting monomeric amyloid in preclinical AD, but the trial showed no significant effect compared to placebo. 4”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [4]
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“The A4 study was a multicenter, Phase 3, double‐blind, placebo‐controlled study in subjects with preclinical AD. 4”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [4]
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Metadata
- Authors
- Sperling, R. A., Donohue, M. C., Raman, R., Rafii, M. S., Johnson, K., Masters, C. L., van Dyck, C. H., Iwatsubo, T., Marshall, G. A., Yaari, R., Mancini, M., Holdridge, K. C., Case, M., Sims, J. R., & Aisen, P. S.
- Affiliations
- University of Southern California (US)
- From the Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School (R.A.S., G.A.M.), and the Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School (K.J.) — both in Boston; Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego (M.C.D., R.R., M.S.R., P.S.A.); the Florey Institute, University of Melbourne, Melbourne, VIC, Australia (C.L.M.); the Departments of Psychiatry, Neurology, and Neuroscience, Yale School of Medicine, New Haven, CT (C.H.D.); the Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo (T.I.); and Eli Lilly, Indianapolis (R.Y., M.M., K.C.H., M.C., J.R.S.).
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-09-21
- Volume
- 389
- Issue
- 12
- Pages
- 1096-1107
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC10559996
- OpenAlex
- W4384523451
- Cited by
- 429
- References
- 36
- Citations by year
- 2026: 140 · 2025: 153 · 2024: 115 · 2023: 21
- FWCI
- 76.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer’s Association
- Accelerating Medicines Partnership through the Foundation for the National Institutes of Health
- GHR Foundation
- Davis Alzheimer Prevention Program
- anonymous foundation
- National Institute on Aging (R01AG063689, U19AG010483, U24AG057437)
- Eli Lilly and Company
- 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 › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- solanezumab, preclinical Alzheimer's disease, amyloid-beta, anti-amyloid monoclonal antibodies, cognitive decline, amyloid PET, 18F-florbetapir, amyloid-related imaging abnormalities, aria, Alzheimer's disease prevention, brain amyloid burden
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Amyloid beta-Peptides, Positron-Emission Tomography, Antibodies, Monoclonal, Humanized
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