Home › Research › Drug development
Plasma pTau-181 Exhibits Flat Longitudinal Trajectories and Weak Cognitive Correlation in UK Biobank: Implications for Anti-Tau Antibody Trial Failures
Lehrer S.. Research Square, 2025-12-01
Topic: Plasma and spinal-fluid biomarkers
Background Monoclonal antibodies targeting pathological tau have repeatedly failed in Alzheimer’s disease (AD) clinical trials. Whether plasma phosphorylated tau (pTau) exhibits dynamic progression or cognitive relevance in population-based cohorts remains unclear. Methods Using UK Biobank, we analyzed 2,523 participants with plasma pTau-181 measured at imaging visits and stratified by APOE ε4 genotype. Mixed-effects models assessed longitudinal pTau-181 slopes. Cross-sectional associations between pTau and fluid intelligence were evaluated with genotype-stratified regression. Results Plasma pTau-181 declined modestly over 4.5 years (− 2.2%/year; p < 0.001). APOE ε4 carriers showed higher baseline pTau (+ 6.4%/allele) but no genotype-specific difference in slope. Fluid intelligence was only weakly and inconsistently associated with pTau-181, with overlapping regression lines across APOE strata. No participants with diagnosed AD had repeated pTau measurements. Conclusions Plasma pTau-181 demonstrates flat or declining longitudinal trajectories and minimal cognitive correlation, suggesting tau is a static biomarker rather than a dynamic therapeutic target in mid-to-late adulthood. These real-world findings help explain why anti-tau monoclonal antibodies have failed to demonstrate clinical efficacy.
Key findings
- Results Plasma pTau-181 declined modestly over 4.5 years (− 2.2%/year; p < 0.001).
- Fluid intelligence was only weakly and inconsistently associated with pTau-181, with overlapping regression lines across APOE strata.
New to this subject? Start with our plain-English guide: Treatments →
Study details
- Study designcross-sectional
- Participants2,523
- Effect size2.2%; 6.4%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 42 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 26 of the 62 points we could judge it on, which is 42 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 2,523 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 26 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 26 of the 62 points we could judge it on is 42 out of 100. |
| Total | 42 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Lehrer, S. (2025). Plasma pTau-181 Exhibits Flat Longitudinal Trajectories and Weak Cognitive Correlation in UK Biobank: Implications for Anti-Tau Antibody Trial Failures. Research Square. https://doi.org/10.21203/rs.3.rs-8204349/v1
Vancouver
Lehrer S. Plasma pTau-181 Exhibits Flat Longitudinal Trajectories and Weak Cognitive Correlation in UK Biobank: Implications for Anti-Tau Antibody Trial Failures. Research Square. 2025. doi:10.21203/rs.3.rs-8204349/v1.
BibTeX
@article{lehrer2025-eaeb6aee,
author = {Lehrer, S.},
title = {{Plasma pTau-181 Exhibits Flat Longitudinal Trajectories and Weak Cognitive Correlation in UK Biobank: Implications for Anti-Tau Antibody Trial Failures}},
journal = {Research Square},
year = {2025},
doi = {10.21203/rs.3.rs-8204349/v1},
url = {https://doi.org/10.21203/rs.3.rs-8204349/v1}
}
Related studies in Drug development
Also tagged “blood-based”
698 studies in the library carry the topic tag “blood-based”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 698 tagged studies.