Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease
Bibliographic record
Abstract
Importance: Developing disease-modifying treatments is a priority for Alzheimer disease research. Objective: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials. Design, Setting, and Participants: This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023. Recruited from 67 sites in the US, Canada, Australia, and Japan, participants included older individuals (age 65-85 years) who were cognitively unimpaired at screening and underwent an amyloid PET scan. Participants without elevated amyloid PET were included from a companion to the A4 study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Exposure: 18F-florbetapir PET imaging. Main Outcomes and Measures: 18F-florbetapir PET imaging was used to classify participants as having elevated amyloid β (Aβ+). Measures of tau included longitudinal plasma p-tau217 and 18F-flortaucipir PET. Cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Results: A total of 1169 individuals were included from A4 Study and 538 without elevated amyloid PET were included from the LEARN Study. Among these 1707 participants, the baseline mean (SD) age was 71.5 (4.7) years, 1024 (60%) were female, and 683 (40%) male; 1169 participants were Aβ+, and the mean (SD) Mini-Mental State Examination score was 28.8 (1.2). The tau PET substudy included 443 participants; plasma p-tau217 levels were available for 1643 participants. The largest effect size of longitudinal tau PET accumulation at 36 months in Aβ+ participants was in the inferior temporal gyrus. Baseline associations with longitudinal change in PACC score in Aβ+ participants were strongest in the entorhinal cortex (correlation [ρ] = -0.55; 95% CI, -0.63 to -0.45) and plasma p-tau217 levels (ρ = -0.47; 95% CI, -0.56 to -0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent cognitive changes. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ2 = 21.7; P < .001) and were not associated with concurrent cognitive change in the tau PET substudy (ρ = -0.03; 95% CI, -0.23 to 0.16) but were modestly associated with concurrent cognitive changes in the full plasma sample (n = 1119; ρ = -0.24; 95% CI, -0.34 to -0.14). Conclusions and Relevance: This study found that tau PET is valuable for both prognostic and real-time tracking of disease progression. Plasma p-tau217 predicts cognitive changes prior to overt cognitive impairment and can efficiently guide participant selection. Imaging-based tau measures may enhance detection of disease-modifying effects and refine therapeutic targets in future Alzheimer disease trials.
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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 | 0.000 | 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 | 0.001 |
| 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".