Temporal sequence of amyloid and tau PET positivity: <i>APOE</i> -ε4 and sex effects, and implications for Alzheimer’s disease progression
Bibliographic record
Abstract
Abstract Importance Alzheimer’s disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials. Objective To investigate how estimated age at amyloid and tau PET positivity, and the time interval between amyloid and tau PET positivity (“amyloid-tau interval”), relate to symptom onset and clinical progression, and whether APOE- ε4 status and sex modify these associations. Design Longitudinal observational study. Setting Multicenter study using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants ADNI participants with at least one positive amyloid PET scan (n=792) or at least one positive tau PET scan (n=212) were included. Both cognitively unimpaired and impaired individuals were included and all had information on sex, APOE- ε4 status, and longitudinal cognitive assessments. Exposures 18 F-florbetapir or 18 F-florbetaben amyloid PET, 18 F-flortaucipir tau PET, CDR global, CDR-SB. Main outcomes and measures We examined the influence of APOE -ε4 status, sex, and their interaction on the age at biomarker positivity and the amyloid–tau interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset based on biomarker positivity age and the amyloid–tau interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline over five years following symptom onset, by biomarker positivity age and amyloid–tau interval duration. Additional models included interaction terms with sex or APOE -ε4 status. Results APOE- ε,4 carriers and women had earlier amyloid and tau PET positivity ages. APOE- ε,4 carriers, women, and those with older age at amyloid PET positivity had a shorter amyloid-tau interval. An older age at amyloid or tau PET positivity and a shorter amyloid-tau interval predicted earlier symptom onset. An older age at amyloid or tau PET positivity was also associated with slower rate of cognitive decline after symptom onset. The amyloid-tau interval did not influence time until symptom onset after tau PET positivity or rate of cognitive decline. Conclusions and relevance APOE- ε4 and sex influenced the timing of amyloid and tau PET positivity and the amyloid-tau interval, which in turn affected symptom onset and clinical progression. These factors should guide the identification of amyloid-positive individuals at highest risk of rapid AD progression, enabling more efficient selection of participants for clinical trials.
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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 | 0.004 | 0.009 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".