| Title: | Dementia risk prediction in individuals with prediabetes or diabetes: A novel multi-protein score with biological pathway analysis |
| Journal: | General Psychiatry |
| Published: | 1 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41890164/ |
| DOI: | https://doi.org/10.1002/gps3.70010 |
Publication 18401
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Abstract
Background: Individuals with prediabetes or diabetes face elevated dementia risk, yet robust prediction tools and mechanistic insights remain limited.</p>
Aims: This study aimed to develop and validate a protein-based risk score for dementia prediction in this high-risk population while elucidating underlying biological pathways and therapeutic targets.</p>
Methods: Utilising data from 10 433 UK Biobank participants with prediabetes or diabetes and proteomic profiling (2911 plasma proteins measured), we developed a dementia protein risk score in a training set (n = 6514) and validated it in testing (n = 2790) and external cohorts (n = 1129).</p>
Results: In the training set, 23 out of 2911 proteins were selected. In the testing set, compared with the basic model (age and sex, C-index: 0.78; 95% confidence interval [CI] 0.74-0.82), the dementia protein risk score (C-index: 0.84; 95% CI 0.81-0.88) significantly improved the performance in predicting incident dementia (C-index increase: 0.06; 95% CI 0.02-0.12), while cardiovascular risk factors, ageing and dementia incidence risk factors (C-index: 0.80; 95% CI 0.76-0.83) and apolipoprotein E (APOE; age and sex included, C-index: 0.81; 95% CI 0.77-0.85) had no significant improvement. Six key proteins (glial fibrillary acidic protein [GFAP], neurofilament light polypeptide [NEFL], Brevican core protein [BCAN], protein MENT [MENT], APOE and growth/differentiation factor 15 [GDF15]) captured the most predictive power. Pathway analyses implicated extracellular matrix remodelling and cholesterol metabolism, whereas Mendelian randomisation identified causal roles for APOE, haematopoietic prostaglandin D synthase (HPGDS), BAG family molecular chaperone regulator 3 (BAG3) and GDF15. Nine proteins were prioritised as druggable targets, including HPGDS, with existing Food and Drug Administration-approved drugs.</p>
Conclusions: This study establishes a highly accurate protein-based risk score for dementia prediction (including 6-23 proteins) in individuals with prediabetes or diabetes, uncovering actionable biological pathways and therapeutic targets. The findings enable precision risk stratification and accelerate translational opportunities for dementia prevention in this population.</p>
11 Authors
- Yuanyuan Zhang
- Yu Huang
- Junyu Xue
- Yiwei Zhang
- Sisi Yang
- Yanjun Zhang
- Ziliang Ye
- Xiaoqin Gan
- Yiting Wu
- Fanfan Hou
- Xianhui Qin
1 Application
| Application ID | Title |
|---|---|
| 73201 | Identification of residual risks of non-infectious chronic diseases |
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