Tau368 in cerebrospinal fluid is associated with severity of tau pathology load in the Alzheimer’s continuum
Bibliographic record
Abstract
Abstract Background Recent developments in the biomarker field allow Alzheimer’s disease (AD) pathophysiology to be reflected at the preclinical stage. We recently presented an assay targeting tau fragments ending at residue 368, which exhibited a stage‐wise decrease in a ratio with total‐tau. The tau368/T‐tau ratio also correlated with tau positron emission tomography (PET) uptake, and was present in tau tangles. In this study, we aimed to validate these findings in a larger cohort including a larger subset spanning the AD continuum. Method We investigated 129 participants cross‐sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (22 young, 60 cognitively unimpaired (CU) elderly (14 Aβ+), 26 mild cognitive impairment (MCI; 10 Aβ+), 14 AD dementia and 7 frontotemporal dementia (FTD)). For all individuals, [18F]AZD4694 and [18F]MK‐6240 PET were used to index Aβ and tau load (Braak stages) respectively. T‐tau was quantified using ELISA (INNOTEST®) and Tau368 was quantified by an in house Single molecule array (Simoa) assay (Quanterix, Billerica, MA). Spearman rank tests assessed correlation between continuous variables. Linear models tested the effect of tau368/t‐tau ratio on PET summary measures and at the voxel level, always adjusting for age and sex. Result Compared to young controls, we observed a stage‐wise decrease of tau368/t‐tau, with the lowest ratio found in AD dementia (P<0.01), followed by CU‐ (P<0.001), CU+ (P<0.01) and MCI‐ (P<0.001). MCI+ had a lower ratio than CU‐ (P<0.01). Furthermore, there was a strong negative correlation between tau368/t‐tau ratio and PET Braak stages in the whole population (I‐II; ρ=‐0.46, P<0.001, III‐IV; ρ=‐0.44, P<0.001, V‐VI; ρ=‐0.37, P<0.001), in MCI+ (I‐II; ρ=‐0.79, P<0.01, III‐IV; ρ=‐0.84, P<0.01, V‐VI; ρ=‐0.83, P<0.01) and in AD dementia (V‐VI; ρ=‐0.57, P<0.05). Voxel‐wise analysis demonstrated strong correlation between tau368/t‐tau and tau PET ligand uptake in the medial and lateral temporal lobes in cognitively impaired individuals, while no significant association was found in CU. Conclusion We provide further evidence of a stage‐wise decrease in CSF tau368/t‐tau, which tracks cortical tau accumulation only in clinically manifest AD dementia and amyloid positive MCI. These results further support that CSF tau368/t‐tau captures severity of tau pathology within the AD continuum.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".