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Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial
Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, Rafii MS, Streffer J et al.. JAMA neurology, 2021-03-01
Topic: Amyloid, tau and blood-test diagnosis
change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P Conclusions and relevance Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial registration ClinicalTrials.gov Identifier: NCT02569398.
Key findings
- change from baseline in Preclinical Alzheimer Cognitive Composite score.
- Secondary change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score.
- Safety was monitored throughout the study.
- Results Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years.
- In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months.
Why it matters
In 557 people with preclinical Alzheimer disease, atabecestat 25 mg was linked to worse thinking scores than placebo by month 6, and the authors report worsening as early as 3 months along with neuropsychiatric side effects. Dosing was stopped early in May 2018 because of liver-related adverse events; after 6 months off the drug there was "evidence of reversibility." The trial gives no sign of benefit and documents early harm from this drug.
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Study details
- Participants189
- Effect size61.2%
- Evidence strengthHigh
How this study scored 73/100
Published in a leading specialty journal, and it is a large phase 3 trial.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A large phase 3 trial (from PubMed type “Clinical Trial, Phase III”) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 2 / 4 | 189 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 1 / 2 | Randomised (as stated in the record) |
| Times cited | 5 / 7 | Cited 112 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.0 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 4 / 6 | Cited 11.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 3 / 4 | Cited 59 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Gary J. Romano: h-index 23 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Brigham and Women's Hospital: institution h-index 1,995 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33464300) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 73 / 100 | — |
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Read the original
- DOI: 10.1001/jamaneurol.2020.4857
- PubMed: 33464300
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Sperling, R., Henley, D., Aisen, P. S., Raman, R., Donohue, M. C., Ernstrom, K., et al. (2021). Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. JAMA neurology. https://doi.org/10.1001/jamaneurol.2020.4857
Vancouver
Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, et al. Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. JAMA neurology. 2021. doi:10.1001/jamaneurol.2020.4857. PMID: 33464300.
BibTeX
@article{sperling2021-33464300,
author = {Sperling, R. and Henley, D. and Aisen, P. S. and Raman, R. and Donohue, M. C. and Ernstrom, K. and Rafii, M. S. and Streffer, J. and others},
title = {{Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial}},
journal = {JAMA neurology},
year = {2021},
doi = {10.1001/jamaneurol.2020.4857},
pmid = {33464300},
url = {https://doi.org/10.1001/jamaneurol.2020.4857}
}
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