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Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer’s disease
Park J, Le Guen Y, Peña-Tauber A, Greicius MD.. medRxiv, 2026-07-10
Topic: Genetics and APOE
Most plasma proteomic studies in Alzheimer’s disease (AD) compare cases and controls cross-sectionally, leaving unresolved which AD-associated proteins mark diagnostic states and which are linked to disease progression. Using longitudinal SomaScan profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples, 7,362 aptamers), we separated baseline AD differences from AD-specific change over time. Linear mixed-effects models requiring concordant baseline and AD-by-time effects defined a 30-protein signature. We prioritized proteins across five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, independent prospective replication in UK Biobank and genetic support from Mendelian randomization and rare-variant burden. Thirteen proteins were supported in two or more domains and six in three. EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence. Signature proteins aligned more strongly with tau and neuronal-injury markers than with A β 42/40. ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature. By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.
Key findings
- Thirteen proteins were supported in two or more domains and six in three.
- EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence.
- Signature proteins aligned more strongly with tau and neuronal-injury markers than with A β 42/40.
- ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature.
- By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.
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Study details
- Study designlongitudinal study
- Participants13,449
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 47 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for 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 29 of the 62 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over 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 | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 4 / 4 | 13,449 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 | 29 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 62 points we could judge it on is 47 out of 100. |
| Total | 47 / 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 →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Park, J., Le Guen, Y., Peña-Tauber, A., & Greicius, M. D. (2026). Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer’s disease. medRxiv. https://doi.org/10.64898/2026.07.01.26356385
Vancouver
Park J, Le Guen Y, Peña-Tauber A, Greicius MD. Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer’s disease. medRxiv. 2026. doi:10.64898/2026.07.01.26356385.
BibTeX
@article{park2026-b642d501,
author = {Park, J. and Le Guen, Y. and Peña-Tauber, A. and Greicius, M. D.},
title = {{Longitudinal plasma proteomics separates diagnostic differences from progression-linked changes in Alzheimer’s disease}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.07.01.26356385},
url = {https://doi.org/10.64898/2026.07.01.26356385}
}