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9 reviewsIntroduction: Type 2 diabetes (T2D) significantly increases dementia risk, yet the molecular mechanismsunderlying this association remain unclear.Objectives: This study aimed to identify protein signatures that distinguish dementia risk in T2D patients,develop a proteomic prediction model, and elucidate biological pathways connecting T2D and dementia.Methods: We analyzed 2,920 plasma proteins from 52,958 participants (including 3,292 with T2D) in theKeywords:UK Biobank Pharma Proteomics Project with a median follow-up of 14.6 years. Cox regression modelswith interaction terms identified T2D-specific protein associations with dementia risk. Machine learningProteomicsmodels were developed to predict dementia in T2D patients. Pathway analysis and weighted gene coDiabetesexpression network analysis identified biological mechanisms linking T2D and dementia.Dementiaproteins with significant interaction effects between T2D and dementia risk. InResults: We identified 471Alzheimer’s diseaseIL6-JAK-STAT3non-T2D individuals, elevated levels of neuronal pentraxin receptor (NPTXR, HR = 0.74, 95 %CI:0.66–0.83)⁎ Corresponding author at: Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053,China.E-mail address: [email protected] (J. Jia). 1 These authors contributed equally: Zhibo Wang, Yuye Ning, Peiyang Gao. 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University.This is an open access article under the CC BY-NC-ND license ( cite this article as: Z. Wang, Y. Ning, P. Gao et al., Proteomic signature of dementia risk in type 2 diabetes, Journal of Advanced Research, Wang, Y. Ning, P. Gao et al. Journal of Advanced Research xxx (xxxx) xxxand carbonic anhydrase14(CA14, HR = 0.67, 95 %CI:0.60–0.75) were exclusively associated withdecreased dementia risk. Cversely, in T2D patients, elevated rho guanine nucl