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Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome
Sofia E. Perfetto, Myuri T. Ruthirakuhan, Si Won Ryoo, Yuen Yan Wong, Lisa Y. Xiong, Natasha Z. Anita, Nathanael A. Caveney, Landon J. Edgar et al.. Journal of Neurochemistry, 2025-12-01
Topic: Risk, prevention and care in population studies
Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk. Pathophysiological mechanisms are not fully understood. In this prospective study of UK Biobank participants, (n = 9943 without T2DM, age = 56.3 ± 8.2 years, 55% female, n = 3752 with T2DM, age = 59.1 ± 7.7 years, 41% female), T2DM was associated with poorer attention (Hedges' g = -0.15[-0.17, -0.10]), processing speed (Hedges' g = -0.14[-0.17, -0.09]), and a higher risk of incident dementia over 15 years (HR = 2.13[1.74, 2.61]). Among 2923 proteins measured by Olink proteomics, 1739 were differentially expressed in T2DM. Four-way decomposition models of proteomic markers, and KEGG pathway analyses, were used to identify potential mediating and moderating effects of biological pathways on the association between T2DM and cognitive or dementia outcomes. For dementia, 230 protein mediators implicated inflammatory pathways (complement/coagulation cascades, cytokine-cytokine receptor interactions, and the janus kinase-signal transducer and activator of transcription signaling pathway), and 11 proteins implicated cholesterol/lipid metabolism as moderators (including apolipoprotein E, low-density lipoprotein receptor and prostaglandin reductase 1). Mediators with the highest accuracy to predict incident dementia in T2DM were glial fibrillary acidic protein (AUC = 0.71[0.67, 0.76]) and neurofilament light polypeptide (AUC = 0.71 [0.67, 0.75]). Multivariate proteomic/clinical models (AUC = 0.78 [0.75, 0.81]) improved accuracy beyond clinical risk factors alone (AUC = 0.74 [0.69, 0.78]). Subgroup analyses by sex, apolipoprotein E ε4 carrier status and age showed some features unique within strata. This study suggests potential targets within inflammatory, oxidative, angiogenesis-related, and metabolic pathways to mitigate cognitive decline and dementia risk in T2DM.
Key findings
- Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk.
- In this prospective study of UK Biobank participants, (n = 9943 without T2DM, age = 56.3 ± 8.2 years, 55% female, n = 3752 with T2DM, age = 59.1 ± 7.7 years, 41% female), T2DM was associated with poorer attention (Hedges' g = -0.15[-0.17, -0.10]), processing speed (Hedges' g = -0.14[-0.17, -0.09]), and a higher risk of incident dementia over 15 years (HR = 2.13[1.74, 2.61]).
Why it matters
In this prospective UK Biobank study, type 2 diabetes was linked to poorer attention, slower processing speed and higher dementia risk over 15 years, with many proteins and inflammatory pathways identified as possible mediators. These findings point to biological pathways but do not show that any treatment or protein target prevents dementia.
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Study details
- Participants9,943
- Effect sizeHR = 2.13; AUC = 0.71; AUC = 0.78
- Evidence strengthLow
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neurochemistry) |
| Journal's citation record | 3 / 4 | Journal of Neurochemistry: journal h-index 349 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 9,943 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | 2 / 7 | Cited 8 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 5.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Walter Swardfager: h-index 47 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Toronto: institution h-index 1,923 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41342355) |
| Free to read | 2 / 2 | Free to read |
| Total | 51 / 100 | — |
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Read the original
- DOI: 10.1111/jnc.70306
- PubMed: 41342355
- Original source →
- Free full text: Journal of Neurochemistry →
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
Perfetto, S. E., Ruthirakuhan, M. T., Ryoo, S. W., Wong, Y. Y., Xiong, L. Y., Anita, N. Z., et al. (2025). Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome. Journal of Neurochemistry. https://doi.org/10.1111/jnc.70306
Vancouver
Perfetto SE, Ruthirakuhan MT, Ryoo SW, Wong YY, Xiong LY, Anita NZ, et al. Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome. Journal of Neurochemistry. 2025. doi:10.1111/jnc.70306. PMID: 41342355.
BibTeX
@article{perfetto2025-41342355,
author = {Perfetto, Sofia E. and Ruthirakuhan, Myuri T. and Ryoo, Si Won and Wong, Yuen Yan and Xiong, Lisa Y. and Anita, Natasha Z. and Caveney, Nathanael A. and Edgar, Landon J. and others},
title = {{Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome}},
journal = {Journal of Neurochemistry},
year = {2025},
doi = {10.1111/jnc.70306},
pmid = {41342355},
url = {https://doi.org/10.1111/jnc.70306}
}
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