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Soluble amyloid composition links proximal APP processing, fibrillar burden and the p-tau181 response
Rodriguez-Espinosa N.. Research Square, 2026-10-22
Topic: Plasma and spinal-fluid biomarkers
Amyloid biomarkers sample distinct levels of an open, kinetically coupled biochemical system, yet scalar summaries may obscure biologically relevant configuration. We asked whether separating shared soluble-peptide variation from Aβ42-selective depletion preserves information and clarifies the amyloid context of the soluble tau response. In 380 Alzheimer’s Disease Neuroimaging Initiative participants, CSF Aβ38, Aβ40 and Aβ42 mass-spectrometry measurements were used to derive two peptide-only analytical constructs: variation shared by Aβ38 and Aβ40 (T), and Aβ42-selective depletion relative to their joint profile (D42). BACE activity and sAPPβ preferentially aligned with T (incremental-R² separation 0.463; 95% bootstrap interval 0.361–0.535). D42 was preferentially associated with later fibrillar burden: among 91 participants with PET a median 4.98 years later, the D42–T contrast was 31.21 Centiloids/SD (95% CI 11.12–51.30). In 375 participants, p-tau181 was independently associated with both constructs (standardized coefficients 0.518 and 0.472), mapping across the T–D42 state space and revealing a supported region of elevated soluble tau. Information-retention analyses showed that tested scalar compressions discarded readout-relevant information. Together, these findings support a two-coordinate representation of soluble amyloid state that preserves biologically relevant information obscured by scalar summaries and locates the soluble tau response within the joint peptide configuration.
Key findings
- D42 was preferentially associated with later fibrillar burden: among 91 participants with PET a median 4.98 years later, the D42–T contrast was 31.21 Centiloids/SD (95% CI 11.12–51.30).
- In 375 participants, p-tau181 was independently associated with both constructs (standardized coefficients 0.518 and 0.472), mapping across the T–D42 state space and revealing a supported region of elevated soluble tau.
- Information-retention analyses showed that tested scalar compressions discarded readout-relevant information.
- Together, these findings support a two-coordinate representation of soluble amyloid state that preserves biologically relevant information obscured by scalar summaries and locates the soluble tau response within the joint peptide configuration.
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Study details
- Participants91
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 27 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and 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 17 of the 62 points we could judge it on, which is 27 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 | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| 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 | 1 / 4 | 91 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| 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 | 17 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 17 of the 62 points we could judge it on is 27 out of 100. |
| Total | 27 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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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
Rodriguez-Espinosa, N. (2026). Soluble amyloid composition links proximal APP processing, fibrillar burden and the p-tau181 response. Research Square. https://doi.org/10.21203/rs.3.rs-10955863/v1
Vancouver
Rodriguez-Espinosa N. Soluble amyloid composition links proximal APP processing, fibrillar burden and the p-tau181 response. Research Square. 2026. doi:10.21203/rs.3.rs-10955863/v1.
BibTeX
@article{rodriguezespinosa2026-415c6827,
author = {Rodriguez-Espinosa, N.},
title = {{Soluble amyloid composition links proximal APP processing, fibrillar burden and the p-tau181 response}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10955863/v1},
url = {https://doi.org/10.21203/rs.3.rs-10955863/v1}
}