P1‐030: Evaluation of translational Alzheimer's disease biomarkers in the aged dog: The effects of age and bace inhibition on CSF amyloid
Bibliographic record
Abstract
Aged dogs demonstrate both cognitive decline and neuropathology that models the spectrum of successful aging through early Alzheimer's disease (AD). The present study sought to further refine the aged canine model by characterizing the effects of age and BACE inhibition on CSF Aß42. CSF was obtained from young (2-4 y), middle-aged (6-8 y) and old (>10 y) Beagle dogs, and was frozen until Aß42 was measured by ELISA. Each of the three age groups were then divided randomly into 3 dose groups (3, 10 and 30 mg/kg) and received a proprietary BACE inhibitor two days following the baseline CSF draw. CSF samples were collected 3 hours following dosing. Aß42 levels in the old group were significantly reduced compared to both young and middle-aged dogs. Aß42 was also reduced significantly following treatment with the BACE inhibitor. A significant interaction between treatment and age was also found, which reflected both lower basal levels of Aß42 in old dogs, as well a non-significant treatment effect in the aged dogs. By contrast, Aß42 levels were reduced by BACE inhibitor treatment in both young and middle-aged dogs. Analysis of percent change revealed a significant effect of dose, which was due to the largest reductions under the high dose. These findings demonstrate that CSF levels of Aß42 are affected by both age and BACE inhibition. The proprietary BACE inhibitor dose dependently lowered CSF Aß42 in the same dogs and was well tolerated, demonstrating the aged dog is a robust model system for examining therapeutics targeting Aß. This effect, however, was least robust in old dogs, which may be due to the lower basal levels of CSF Aß42 in this age group. These results reveal a cross-sectional biomarker pattern that parallels that seen in the clinical progression to AD. This observation is further supported by elevated CSF phospho-tau in aged compared to young dogs. Further longitudinal examination of various translational biomarkers in the dog is underway including CSF biomarkers and FDG-PET. The present results further supports use of the aged beagle dog as a natural model for efficacy and safety evaluation of novel AD therapeutics.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".