CSF proteomics of semorinemab Alzheimer’s disease trials identifies cell-type specific signatures
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".