Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals
Bibliographic record
Abstract
<h3>Background and Objectives</h3> To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally. <h3>Methods</h3> In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time. <h3>Results</h3> This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n<sub>CU–</sub> = 197); CU Aβ-positive (n<sub>CU+</sub> = 55), mild cognitively impaired (MCI) Aβ-negative (n<sub>MCI–</sub> = 228), MCI Aβ-positive (n<sub>MCI+</sub> = 193), and AD dementia Aβ-positive (n<sub>AD</sub> = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (<i>p</i> = 0.01), worse brain atrophy (<i>p</i> = 8.8 × 10<sup>−27</sup>), and worse MMSE scores (<i>p</i> = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94–14.80, <i>p</i> = 1.5 × 10<sup>−14</sup>]). Despite the significant association with Aβ pathology (η<sup>2</sup><sub>Aβ PET</sub> = 0.09, <i>P</i><sub>Aβ PET</sub> < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η<sup>2</sup><sub>pTau-181</sub> = 0.53, <i>P</i><sub>pTau-181</sub> < 0.001; η<sup>2</sup><sub>tTau</sub> = 0.59, <i>P</i><sub>tTau</sub> < 0.001). <h3>Discussion</h3> High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".