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α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau
Rodríguez-Baz Í, Ferrer R, Falip MS, Vera-Campuzano E, Sala I, Maure-Blesa L, Selma-González J, García-Castro J et al.. Research Square, 2026-10-22
Topic: Plasma and spinal-fluid biomarkers
Background. Plasma p-tau217 is sufficient to establish a biological diagnosis of Alzheimer's disease (AD) and is and is increasingly used as a routine diagnostic tool. Many patients with AD also carry α-synuclein pathology, detectable by cerebrospinal fluid (CSF) seed amplification assay (αSynSAA). Seeding activity has been linked to more fibrillar tau than amyloid burden alone would predict, but whether this influences plasma p-tau217 levels, or compromises classification at clinical thresholds, is unknown. Methods. Cross-sectional analysis of the Alzheimer's Disease Neuroimaging Initiative. Plasma p-tau217 (Fujirebio Lumipulse) was compared by αSynSAA status conditional on amyloid PET Centiloids, the CSF p-tau181/Aβ42 ratio and tau PET, using generalised additive models adjusted for age, sex, APOE ε4 status and cognitive stage (n = 193, of whom 33 αSynSAA-positive; CSF-referenced n = 286; amyloid PET-referenced n = 246). We quantified the attenuation contributed by each reference measure, modelled fibrillar tau against amyloid and against plasma p-tau217 by seeding status, and reclassified αSynSAA-positive participants after removing the estimated seeding-associated increment. Results. αSynSAA-positive participants had higher plasma p-tau217 levels at a given amyloid PET burden (27.3%, 95% CI 4.9–54.5; p = 0.015) and CSF ratio (22.9%, 1.7–48.7; p = 0.033), but not at a given tau PET burden (12.1%, − 10.3–40.3; p = 0.313); tau PET attenuated the association by 55.4%, more than the CSF ratio (31.1%) or amyloid PET (25.4%). The amyloid–tau relationship was steeper in αSynSAA-positive participants (p = 0.047), yet a given plasma p-tau217 level corresponded to the same fibrillar tau burden in both groups (2.5% higher, − 2.7–8.0; p = 0.347). Removing the increment did not improve agreement with either reference standard and modestly worsened it (accuracy 93.9% to 92.4% against the CSF ratio; 84.6% to 82.7% against amyloid PET), with the loss falling on sensitivity. Conclusions. Plasma p-tau217 is elevated in αSynSAA-positive individuals at equivalent AD pathology measured by amyloid PET or the CSF ratio, and this elevation is attenuated most by fibrillar tau. Neither analysis designed to detect artefactual inflation found evidence of it. A plasma p-tau217 result should not be down-weighted in patients with concomitant Lewy-related pathology.
Key findings
- Results. αSynSAA-positive participants had higher plasma p-tau217 levels at a given amyloid PET burden (27.3%, 95% CI 4.9–54.5; p = 0.015) and CSF ratio (22.9%, 1.7–48.7; p = 0.033), but not at a given tau PET burden (12.1%, − 10.3–40.3; p = 0.313); tau PET attenuated the association by 55.4%, more than the CSF ratio (31.1%) or amyloid PET (25.4%).
- A plasma p-tau217 result should not be down-weighted in patients with concomitant Lewy-related pathology.
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Study details
- Study designcross-sectional
- Participants193
- Effect size27.3%; 22.9%; 12.1%
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 39 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 24 of the 62 points we could judge it on, which is 39 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 | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 193 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 | 24 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 24 of the 62 points we could judge it on is 39 out of 100. |
| Total | 39 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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APA 7th
Í, R.-B., Ferrer, R., Falip, M. S., Vera-Campuzano, E., Sala, I., Maure-Blesa, L., et al. (2026). α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau. Research Square. https://doi.org/10.21203/rs.3.rs-11271891/v1
Vancouver
Í R.-B, Ferrer R, Falip MS, Vera-Campuzano E, Sala I, Maure-Blesa L, et al. α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau. Research Square. 2026. doi:10.21203/rs.3.rs-11271891/v1.
BibTeX
@article{i2026-af4554ea,
author = {Í, Rodríguez-Baz and Ferrer, R. and Falip, M. S. and Vera-Campuzano, E. and Sala, I. and Maure-Blesa, L. and Selma-González, J. and García-Castro, J. and others},
title = {{α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11271891/v1},
url = {https://doi.org/10.21203/rs.3.rs-11271891/v1}
}