Prognostic value of plasma biomarkers in a clinical trial of mild‐to‐moderate Alzheimer’s Disease
Bibliographic record
Abstract
Abstract Background Informative, readily accessible plasma biomarkers of pathology, neuroinflammation, and neurodegeneration in Alzheimer’s disease (AD) could enhance targeted approaches to AD trial design and treatment. In post‐hoc analyses, we examined whether plasma biomarkers (Aβ1‐40, Aβ1‐42, total tau, p‐tau‐181, NfL, and GFAP) predicted 48‐week change in cognitive (ADAS‐Cog11), global function (CDR‐SB), and volumetric MRI (6 cortical regions and 2 whole brain measures) outcomes in T2 Protect AD, a phase‐2 placebo‐controlled RCT of troriluzole in mild‐to‐moderate AD (NCT03605667). Method At least one baseline biomarker measurement was available for 319 of 350 trial participants, forming the analytic sample. No significant treatment effects were found in T2 Protect AD (Feldman 2021, JPAD 8(4):s46); thus, treatment arms were pooled for this analysis. Baseline levels of, and 48‐week changes in, plasma biomarkers were assessed for association with 48‐week change in outcomes using linear regression adjusted for relevant covariates. Combinations of baseline plasma biomarkers that best predicted 48‐week decline on the ADAS‐Cog11 and CDR‐SB were identified using LASSO regression. Statistical significance level was 5%; p‐values were Bonferroni corrected for multiple comparisons. Result Participant characteristics are presented in Table 1. Higher baseline plasma NfL predicted greater 48‐week decline on ADAS‐Cog11 (p = 0.026) and CDR‐SB (p = 0.048; Fig. 1A). LASSO revealed that the combination of baseline plasma NfL, total tau, and Aβ42/40 ratio best predicted 48‐week decline on ADAS‐Cog11, whereas baseline NfL alone best predicted 48‐week decline on CDR‐SB. Regarding MRI outcomes, baseline NfL predicted increase in ventricular volume (p = 0.018; Fig 1A). Baseline NfL, GFAP, and p‐tau‐181 each predicted 48‐week decline in mid‐temporal cortical volume (all p<0.02; Fig.1B); LASSO results were similar. The only significant association between 48‐week biomarker change and clinical outcomes was between increased plasma NfL and worsening CDR‐SB. Conclusion Elevated baseline plasma NfL predicted greater 48‐week decline on cognitive, global function, and MRI measures in a clinical trial of mild‐to‐moderate AD. Furthermore, greater increase in plasma NfL over time was associated with greater clinical decline. Plasma NfL is an easily accessible biomarker that may enhance AD clinical trial design and treatment strategies. Acknowledgement: Trial funding by Biohaven Pharmaceuticals; data and trial coordination by the Alzheimer’s Disease Cooperative Study (ADCS).
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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 | 0.009 | 0.017 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".