Plasma <i>p</i> ‐tau changes across the clinical spectrum of Alzheimer's disease: a systematic review and meta‐analysis
Bibliographic record
Abstract
Abstract Background Alzheimer's disease (AD) plasma biomarkers have transformed the field due to their scalability and minimal invasiveness, especially when evidence of AD biomarker abnormality is required for novel anti‐amyloid immunotherapies. Among plasma biomarker candidates, phosphorylated tau ( p ‐tau) variants show most promise for clinical application. While establishing cutoffs is crucial for implementation, understanding continuous‐level changes is critical for accurate interpretation in research and clinical settings. Given the variety of p ‐tau biomarkers and emerging assays, robust estimates of continuous‐level plasma p ‐tau changes across the clinical spectrum of AD are needed. Method We screened databases for studies (01‐Jul‐1984 to 09‐Dec‐2024) reporting plasma p ‐tau concentrations alongside Aβ‐PET, CSF biomarkers, or neuropathology. Plasma p ‐tau fold‐changes across the AD clinical spectrum were assessed in two analyses: i) from CU Aβ‐ to CU Aβ+, MCI Aβ+, and Aβ+ dementia and (ii) CI Aβ‐positive vs. CI Aβ‐negative. Random‐effects models using the ratio of means method estimated fold‐change effect sizes. This PRISMA‐compliant study was pre‐registered (PROSPERO‐ID: CRD42023422143). Result Of 2112 titles screened, 71 studies were included in this preliminary analysis. Plasma p ‐tau217 showed a stepwise increase across the AD clinical spectrum, increasing 2.17‐fold (95%CI 1.98–2.37) in CU Aβ‐positive ( n = 1451), 3.16‐fold (95%CI 2.84–3.52) in MCI Aβ‐positive ( n = 1185), and 4.95‐fold (95%CI 4.18–5.87) in Aβ‐positive dementia ( n = 925) compared with CU Aβ‐negative ( n = 3973) (Figure 1). When comparing Aβ‐positive CI vs. Aβ‐negative CI individuals, p ‐tau217 increased nearly twice as much (3.58‐fold, 95%CI 3.25–3.93; n = 5995) compared to p ‐tau181 (1.71‐fold, 95%CI 1.61–1.82; n = 8342) and p ‐tau231 (1.71‐fold, 95%CI 1.53–1.90; n = 1019) (Figure 2), and similar to p ‐tau217/np‐tau217 (%p‐tau217: 3.59‐fold, 95%CI 2.74‐4.71; n = 1019). Effect size summaries for each p ‐tau variant across analyses are shown in Figure 3. Sensitivity analyses preserving only the median‐performing assay in head‐to‐head studies led to similar results. Conclusion P ‐tau217 is the plasma biomarker with the largest dynamic range across the entire clinical AD spectrum, with its large AD‐related effect sizes in symptomatic patients making it a robust candidate for clinical implementation. Results do not demonstrate any consistent superiority of %p‐tau217 over p ‐tau217, but few studies used the ratio. Data extraction is ongoing until March/2025. A paired diagnostic accuracy meta‐analysis was also submitted.
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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 | 0.017 | 0.039 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.019 | 0.032 |
| Bibliometrics | 0.007 | 0.010 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.004 | 0.002 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| 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".