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Proteomic markers linking anxiety phenotypes to Alzheimers disease risk: a multi-analyte proteomic analysis
Costa, A. P.; Karim, H. T.; Farinas, M. F.; Geissinger, M. M.; Zeng, X.; Tudorascu, D. L.; Butters, M. A.; Karikari et al.. medRxiv (preprint), 2026-09-17
Topic: Amyloid, tau and blood-test diagnosis
ImportanceAnxiety phenotypes - rumination, global anxiety, and worry (RAW) - are increasingly associated with Alzheimers disease and related dementias (ADRD) risk, yet how anxiety phenotypes relate to coordinated, multi-system biology in the at-risk older adults is unknown. ObjectiveTo map associations between anxiety phenotypes and plasma proteomic profile across five ADRD-relevant biological domains in older adults with high anxiety symptoms. Design, Setting, and ParticipantsCross-sectional analysis of 110 older adults (aged 53-75 years) without dementia from the observational longitudinal RAW Brain study in Pittsburgh, Pennsylvania. Main Outcome(s) and Measure(s)Plasma was profiled with the NULISAseq CNS panel. Principal component (PC) analysis was conducted with Horns parallel analyses across five ADRD-relevant biological domains (amyloid/tau pathology, inflammation, neurodegeneration, synuclein/synaptic disorders, and vascular) yielded 14 PCs (37.4-64.9% within-domain variance). Associations with each phenotype were tested by linear regression adjusted for age and sex, with Benjamini-Hochberg false discovery rate correction (p-FDR<0.05). ResultsA neurodegeneration component (higher neuronal pentraxins and neurofilament light, with lower neurogranin) was associated with all three phenotypes (rumination, {beta}=0.26; global anxiety, {beta}=0.39; worry, {beta}=0.36; all p-FDR<0.05). Inflammatory, VEGF receptor-ligand, and phospho-tau versus amyloid-processing components showed phenotype-specific associations, most often with worry severity. Conclusion and RelevanceDistinct anxiety phenotypes map onto dissociable plasma proteomic profiling, converging on a shared neurodegeneration axis reflecting neuronal injury, while diverging across neuroimmune, vascular, and proteostatic domains. These results point toward the biological heterogeneity of anxiety phenotypes as risk factors for ADRD. Further research is needed to clarify these biological pathways and explore targeted prevention strategies.
Key findings
- ImportanceAnxiety phenotypes - rumination, global anxiety, and worry (RAW) - are increasingly associated with Alzheimers disease and related dementias (ADRD) risk, yet how anxiety phenotypes relate to coordinated, multi-system biology in the at-risk older adults is unknown.
- ResultsA neurodegeneration component (higher neuronal pentraxins and neurofilament light, with lower neurogranin) was associated with all three phenotypes (rumination, {beta}=0.26; global anxiety, {beta}=0.39; worry, {beta}=0.36; all p-FDR<0.05).
- Inflammatory, VEGF receptor-ligand, and phospho-tau versus amyloid-processing components showed phenotype-specific associations, most often with worry severity.
- These results point toward the biological heterogeneity of anxiety phenotypes as risk factors for ADRD.
Why it matters
In 110 older adults without dementia, anxiety-related traits such as rumination and worry were linked to a pattern of blood proteins related to neurodegeneration. This is cross-sectional observational research and does not show whether treating anxiety would reduce dementia risk.
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Study details
- Study designlongitudinal study
- Effect size64.9%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 32 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size, studied in people and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 30 of the 94 points we could judge it on, which is 32 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| 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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.5 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Carmen Andreescu: h-index 40 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Pittsburgh: institution h-index 1,470 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 30 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 30 of the 94 points we could judge it on is 32 out of 100. |
| Total | 32 / 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
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Costa, A. P., Karim, H. T., Farinas, M. F., Geissinger, M. M., Zeng, X., Tudorascu, D. L., et al. (2026). Proteomic markers linking anxiety phenotypes to Alzheimers disease risk: a multi-analyte proteomic analysis. medRxiv (preprint). https://doi.org/10.64898/2026.09.16.26363134
Vancouver
Costa AP, Karim HT, Farinas MF, Geissinger MM, Zeng X, Tudorascu DL, et al. Proteomic markers linking anxiety phenotypes to Alzheimers disease risk: a multi-analyte proteomic analysis. medRxiv (preprint). 2026. doi:10.64898/2026.09.16.26363134.
BibTeX
@article{costa2026-7fcc0d53,
author = {Costa, A. P. and Karim, H. T. and Farinas, M. F. and Geissinger, M. M. and Zeng, X. and Tudorascu, D. L. and Butters, M. A. and Karikari and others},
title = {{Proteomic markers linking anxiety phenotypes to Alzheimers disease risk: a multi-analyte proteomic analysis}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.16.26363134},
url = {https://doi.org/10.64898/2026.09.16.26363134}
}
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