Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease
Why this work is in the frame
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Bibliographic record
Abstract
<title>Abstract</title> Biomarkers for early phosphorylation of tau constitute an unmet need for disease modifying intervention in early stages of Alzheimer’s disease (AD). Recent advances in targeted mass spectrometry and immunoassays have revealed phosphorylation sites, in the cerebrospinal fluid (CSF), with potentially greater utility as preclinical and diagnostic biomarkers as compared to the well validated biomarker – phosphorylated tau at threonine 181 (p-tau181). Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are highly accurate biomarkers for Alzheimer’s disease (AD) neuropathology and are already increased before cognitive symptoms have manifested. However, it is unknown if these preclinical increases transpire earlier, prior to amyloid-beta (Aβ) positivity threshold, and if an ordinal sequence of p-tau epitopes occurs at this incipient phase. In this study, we measured cerebrospinal (CSF) p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum compared to AD neuropathology as indexed by Ab ([<sup>18</sup>F]AZD4694) and tau ([<sup>18</sup>F]MK6240) position emission tomography. CSF P-tau217 and p-tau231 predicted Aβ and tau at the preclinical and dementia stages to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was more sensitive to the earliest changes in Aβ in the medial orbitofrontal, precuneus and posterior cingulate cortices before global Aβ PET positivity had been achieved. Our findings demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.003 |
| 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 it