Exploring the utility of Plasma GFAP as a secondary endpoint in Alzheimer's disease Clinical trials to monitor disease progression
Bibliographic record
Abstract
Abstract Background Recent anti‐amyloid clinical trials have incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint, reporting a notable decrease in plasma GFAP levels over time. Additionally, plasma GFAP has been associated with Aβ pathology and cognitive decline in individuals with cognitive impairment, making it a robust biomarker of neuroinflammation for Alzheimer’s disease (AD). Here, we tested the utility of changes in plasma GFAP as a secondary endpoint in AD clinical trials focusing on cognitively impaired (CI) individuals. Method We evaluated CI Aβ+ individuals from two distinct cohorts: TRIAD (n=29, mean age (SD) = 71.5 (6.48), %MCI=44.8 and BICWALZS (n=65, mean age (SD) = 71.5 (6.48), %MCI=66.1]. All individuals had Aβ PET measurements at baseline. Paired t‐tests compared plasma GFAP levels between baseline and follow‐up. Cox proportional‐hazards analysis was performed to assess whether changes in plasma GFAP levels were predictive of increased odds for increasing CDR sum of boxes score over time. Sample size estimation was based on a hypothesized 25% drug effect on plasma GFAP reduction. Result We found a significant increase in plasma GFAP levels compared to baseline in both cohorts (Figures 1A and 1B). The percentage change in the research‐based cohort was slightly higher, likely attributed to a higher proportion of AD individuals compared to the memory clinic cohort (Figure 1C). Longitudinal plasma GFAP was associated with an increased risk of worsening cognition over time (Figures 2A and 2B). The effect size was slightly higher in the memory clinic cohort likely due to a relatively smaller standard deviation (Figure 3A). Inclusion of CI Aβ + individuals in a clinical trial testing a hypothesized 25% drug effect would necessitate 1354 participants in the research‐based cohort and 977 participants in the memory clinic cohort per study arm (Figure 3B). Conclusion Changes in GFAP are associated with worsening cognition over time in CI Aβ + individuals. Our findings suggest Plasma GFAP as a robust biomarker to be used as a secondary endpoint to monitor disease progression in CI Aβ + in AD clinical trials. Our findings, replicated in both research and clinical settings, may have implications in AD clinical trials composed of a real‐world population.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.007 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 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 teacher head, 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".