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Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, Shaw LM, Masters CL et al.. Neurology, 2021-12-14
Topic: Amyloid, tau and blood-test diagnosis
Background and objectives To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols. Methods Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40. Results In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals. Discussion Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials. Classification of evidence This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.
Key findings
- Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.
- Results In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91).
- These findings were consistent across the 3 cohorts, despite differences in protocols.
Why it matters
In 465 people from research cohorts in the US, Australia and Sweden, whose clinics collected and processed blood differently, one mass-spectrometry blood test (plasma Aβ42/Aβ40) agreed well with amyloid PET scans (AUC 0.84, rising to 0.88 when APOE ε4 status was added) and with spinal-fluid tests (AUC 0.85, rising to 0.93). The authors report that results were consistent across all three cohorts and similar in people with and without memory problems, so the test could help flag brain amyloid without a scan or lumbar puncture. It detects plaques, not dementia. It still misclassifies some people and is not a treatment.
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Study details
- Participants465
- Effect sizeAUC 0.88
- Evidence strengthModerate
How this study scored 67/100
Published in a leading specialty journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 2 / 4 | 465 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 188 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.3 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 5 / 6 | Cited 21.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 12 other studies in this library |
| Still being cited | 3 / 4 | Cited 102 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Randall John Bateman: h-index 101 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34906975) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 67 / 100 | — |
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Read the original
- DOI: 10.1212/wnl.0000000000013211
- PubMed: 34906975
- 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
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Li, Y., Schindler, S. E., Bollinger, J. G., Ovod, V., Mawuenyega, K. G., Weiner, M. W., et al. (2022). Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. https://doi.org/10.1212/wnl.0000000000013211
Vancouver
Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, et al. Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology. 2022. doi:10.1212/wnl.0000000000013211. PMID: 34906975.
BibTeX
@article{li2022-34906975,
author = {Li, Y. and Schindler, S. E. and Bollinger, J. G. and Ovod, V. and Mawuenyega, K. G. and Weiner, M. W. and Shaw, L. M. and Masters, C. L. and others},
title = {{Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques}},
journal = {Neurology},
year = {2022},
doi = {10.1212/wnl.0000000000013211},
pmid = {34906975},
url = {https://doi.org/10.1212/wnl.0000000000013211}
}
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