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Proteomic biomarkers of cognitive function, APOE ε4 status, and dementia in Generation Scotland
Smith HM, Moodie JE, Davies G, Richmond A, Robertson JA, Chybowska AD, Drake C, Adkin P et al.. medRxiv, 2026-01-29
Topic: Genetics and APOE
Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry–derived proteomic correlates of cognitive function, genetic predisposition to cognitive health, APOE ε4 status, and incident dementia. Using multivariate Bayesian regression, we assessed associations between 439 independent mass spectrometry signals and five cognitive outcomes—four cognitive tests and a cognitive function polygenic score—in Generation Scotland (n = 14,258). We observed associations between three cognitive tests (digit symbol, vocabulary and verbal fluency) and a mass spectrometry signal that mapped to selenoprotein P (absolute β range = 0.02 – 0.03, posterior inclusion probability ≥ 0.95). Carrying one or two copies of the APOE ε4 allele was associated with a lower mass spectrometry signal that mapped to afamin (β = -0.08 and -0.2, respectively, p < 3.1 x 10 -4 , n = 14,745). A higher mass spectrometry signal that maps to both complement c2 and complement factor B proteins was associated with lower hazard for incident dementia (hazard ratio = 0.75, p < 3.1 x 10 -4 , n cases = 212 and n controls = 6,765) diagnosed up to 17 years after blood sampling. We identified specific independent mass spectrometry signals which may be candidate biomarkers of cognitive function, APOE ε4 status, and could aid in the early detection of dementia; however, further replication studies in other populations are required.
Key findings
- We observed associations between three cognitive tests (digit symbol, vocabulary and verbal fluency) and a mass spectrometry signal that mapped to selenoprotein P (absolute β range = 0.02 – 0.03, posterior inclusion probability ≥ 0.95).
- Carrying one or two copies of the APOE ε4 allele was associated with a lower mass spectrometry signal that mapped to afamin (β = -0.08 and -0.2, respectively, p < 3.1 x 10 -4 , n = 14,745).
- A higher mass spectrometry signal that maps to both complement c2 and complement factor B proteins was associated with lower hazard for incident dementia (hazard ratio = 0.75, p < 3.1 x 10 -4 , n cases = 212 and n controls = 6,765) diagnosed up to 17 years after blood sampling.
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Study details
- Participants14,258
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 35 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 22 of the 62 points we could judge it on, which is 35 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 | 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 | 4 / 4 | 14,258 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 | 2 / 2 | Free to read |
| Points | 22 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 22 of the 62 points we could judge it on is 35 out of 100. |
| Total | 35 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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APA 7th
Smith, H. M., Moodie, J. E., Davies, G., Richmond, A., Robertson, J. A., Chybowska, A. D., et al. (2026). Proteomic biomarkers of cognitive function, APOE ε4 status, and dementia in Generation Scotland. medRxiv. https://doi.org/10.64898/2026.01.27.26344912
Vancouver
Smith HM, Moodie JE, Davies G, Richmond A, Robertson JA, Chybowska AD, et al. Proteomic biomarkers of cognitive function, APOE ε4 status, and dementia in Generation Scotland. medRxiv. 2026. doi:10.64898/2026.01.27.26344912.
BibTeX
@article{smith2026-2d2f572b,
author = {Smith, H. M. and Moodie, J. E. and Davies, G. and Richmond, A. and Robertson, J. A. and Chybowska, A. D. and Drake, C. and Adkin, P. and others},
title = {{Proteomic biomarkers of cognitive function, APOE ε4 status, and dementia in Generation Scotland}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.01.27.26344912},
url = {https://doi.org/10.64898/2026.01.27.26344912}
}
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