Tau phosphorylation is more closely associated with amyloid‐β plaques than with tau neurofibrillary tangles
Bibliographic record
Abstract
Abstract Background While fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer’s Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles. Method We studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer’s clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI). Result We observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman’s R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package “Cocor”, for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort. Conclusion Phosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.003 | 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".