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Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers
Linda Karlsson, Shorena Janelidze, Nicolas R. Barthélemy, Kanta Horie, Joseph Therriault, Lorenzo Gaetani, Giovanni Bellomo, Suzanne Elizabeth Schindler et al.. Brain, 2025-10-03
Topic: Amyloid, tau and blood-test diagnosis
Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR2 = 0.064-0.24) and Aβ-PET (ΔR2 = 0.016-0.28). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R2 = 0.78, compared with 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R2 = 0.65, compared with 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR2 = 0.004-0.14), with the strongest effect for eMTBR-tau243/np-tau (R2 = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR2 = 0.018-0.16, strongest for p-tau217/np-tau: R2 = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced interindividual rather than intra-individual variability over time. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.
Key findings
- Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models.
- CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR2 = 0.064-0.24) and Aβ-PET (ΔR2 = 0.016-0.28).
- The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R2 = 0.78, compared with 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R2 = 0.65, compared with 0.46 for non-normalized p-tau217).
- Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR2 = 0.004-0.14), with the strongest effect for eMTBR-tau243/np-tau (R2 = 0.72 versus 0.60).
- Associations with Aβ-PET were enhanced with np-tau normalization (ΔR2 = 0.018-0.16, strongest for p-tau217/np-tau: R2 = 0.62 versus 0.53).
Why it matters
Dividing certain Alzheimer's fluid biomarkers by reference proteins such as Aβ40 or np-tau strengthened their link to amyloid and tau PET scans in a large cohort. This is a measurement improvement that could make blood and spinal fluid tests more accurate, not a treatment or cure.
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Study details
- Study designlongitudinal study
- Participants1,702
- Effect size50.7%
- Evidence strengthModerate
How this study scored 63/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| 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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,702 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 | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Oskar Hansson: h-index 148 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 22 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41051312) |
| Free to read | 2 / 2 | Free to read |
| Total | 63 / 100 | — |
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Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Karlsson, L., Janelidze, S., Barthélemy, N. R., Horie, K., Therriault, J., Gaetani, L., et al. (2025). Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers. Brain. https://doi.org/10.1093/brain/awaf375
Vancouver
Karlsson L, Janelidze S, Barthélemy NR, Horie K, Therriault J, Gaetani L, et al. Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers. Brain. 2025. doi:10.1093/brain/awaf375. PMID: 41051312.
BibTeX
@article{karlsson2025-41051312,
author = {Karlsson, Linda and Janelidze, Shorena and Barthélemy, Nicolas R. and Horie, Kanta and Therriault, Joseph and Gaetani, Lorenzo and Bellomo, Giovanni and Schindler, Suzanne Elizabeth and others},
title = {{Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers}},
journal = {Brain},
year = {2025},
doi = {10.1093/brain/awaf375},
pmid = {41051312},
url = {https://doi.org/10.1093/brain/awaf375}
}
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