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CSF proteomics of semorinemab Alzheimer's disease trials identifies cell-type specific signatures
Alyaa M Abdel-Haleem, Ellen Casavant, Balazs Toth, Edmond Teng, Cecilia Monteiro, Nikhil J Pandya, Caspar Glock, Casper C Hoogenraad et al.. Brain : a journal of neurology, 2026-01-08
Topic: Disease mechanisms in lab and animal studies
Targeting of tau pathology has long been proposed as a potential therapeutic strategy for Alzheimer's disease (AD). Semorinemab is a humanized IgG4 monoclonal antibody that binds to all known isoforms of full-length tau with high affinity and specificity. Semorinemab's safety and efficacy have been studied in two phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trials: Tauriel (prodromal-to-mild AD; NCT03289143; in which semorinemab failed to demonstrate clinical efficacy) and Lauriet (mild-to-moderate AD; NCT03828747. However, semorinemab was associated with a significant slowing in progression in a co-primary end point of cognition only in Lauriet but not in Tauriel. Proteomic profiling of CSF collected in these trials was performed to gain a better understanding of the effect of semorinemab in light of the different clinical outcomes. CSF was collected from a subset of patients at baseline and after 49 or 73 weeks in Tauriel and baseline and after 49 or 61 weeks in Lauriet. Samples were analysed using single-shot field asymmetric ion mobility spectrometry-data independent acquisition-mass spectrometry (FAIMS-DIA-MS) and analysed with Spectronaut and MS Stats. Proteomics results were integrated with publicly available single-nucleus brain datasets to contextualize cellular expression profiles of differentially expressed proteins. A novel proteomics dataset was generated using more than 250 CSF samples where more than 3500 proteins were detected. Treatment-associated proteomic signatures were defined for each clinical trial as the set of proteins significantly elevated in the treatment arm in the respective trial. Integration of the corresponding gene signatures with brain single-nucleus RNA-sequencing datasets from AD and healthy age-matched controls revealed that the Lauriet signature genes were enriched in microglia, while Tauriel signature genes were more broadly expressed across brain cell types. Furthermore, the Lauriet gene signature was significantly upregulated in microglia from AD patients compared to non-demented controls. The elevation of proteins such as CHI3L1 and GPNMB with treatment suggested an activated glial state. This study demonstrates the utility of CSF clinical proteomics to assess the pharmacodynamic response of semorinemab and contributes to our understanding of how an anti-tau antibody influences disease-relevant pathophysiology in AD.
Key findings
- However, semorinemab was associated with a significant slowing in progression in a co-primary end point of cognition only in Lauriet but not in Tauriel.
- Proteomics results were integrated with publicly available single-nucleus brain datasets to contextualize cellular expression profiles of differentially expressed proteins.
- Treatment-associated proteomic signatures were defined for each clinical trial as the set of proteins significantly elevated in the treatment arm in the respective trial.
- Integration of the corresponding gene signatures with brain single-nucleus RNA-sequencing datasets from AD and healthy age-matched controls revealed that the Lauriet signature genes were enriched in microglia, while Tauriel signature genes were more broadly expressed across brain cell types.
- Furthermore, the Lauriet gene signature was significantly upregulated in microglia from AD patients compared to non-demented controls.
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Study details
- Study designclinical trial
- Evidence strengthHigh
How this study scored 84/100
Published in a leading specialty journal, and it is a randomised controlled trial. Scored zero for sample size and effect reported because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 47 of the 56 points we could judge it on, which is 84 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 11 / 12 | A randomised controlled trial (from PubMed type “Randomized Controlled Trial”) |
| 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 | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40435316) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 47 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 47 of the 56 points we could judge it on is 84 out of 100. |
| Total | 84 / 100 | — |
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APA 7th
Abdel-Haleem, A. M., Casavant, E., Toth, B., Teng, E., Monteiro, C., Pandya, N. J., et al. (2026). CSF proteomics of semorinemab Alzheimer's disease trials identifies cell-type specific signatures. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaf200
Vancouver
Abdel-Haleem AM, Casavant E, Toth B, Teng E, Monteiro C, Pandya NJ, et al. CSF proteomics of semorinemab Alzheimer's disease trials identifies cell-type specific signatures. Brain : a journal of neurology. 2026. doi:10.1093/brain/awaf200. PMID: 40435316.
BibTeX
@article{abdelhaleem2026-40435316,
author = {Abdel-Haleem, Alyaa M and Casavant, Ellen and Toth, Balazs and Teng, Edmond and Monteiro, Cecilia and Pandya, Nikhil J and Glock, Caspar and Hoogenraad, Casper C and others},
title = {{CSF proteomics of semorinemab Alzheimer's disease trials identifies cell-type specific signatures}},
journal = {Brain : a journal of neurology},
year = {2026},
doi = {10.1093/brain/awaf200},
pmid = {40435316},
url = {https://doi.org/10.1093/brain/awaf200}
}