Skip to main content
ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #430681
Research Project: Utilizing Precision Approaches to Refine Dietary Guidance of Americans to Reduce Chronic Disease

Location: Obesity and Metabolism Research

Title: Type 2 diabetes mellitus, cognitive performance, and incident dementia; identifying mediating pathways and biomarkers from the plasma proteome

Author
item PERFETTO, SOFIA - University Of Toronto
item RUTHIRAKUHAN, MYURI - University Of Toronto
item RYOO, SI - University Of Toronto
item WONG, YUEN - University Of Toronto
item XIONG, LISA - University Of Toronto
item ANITA, NATASHA - University Of California, San Diego
item CAVENEY, NATHANAEL - University Of Toronto
item EDGAR, LANDON - University Of Toronto
item Newman, John
item COGO-MOREIRA, HUGO - Ostfold University College
item SWARDFAGER, WALTER - University Of Toronto

Submitted to: Journal of Neurochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/1/2025
Publication Date: 12/4/2025
Citation: Perfetto, S.E., Ruthirakuhan, M., Ryoo, S.W., Wong, Y.Y., Xiong, L.Y., Anita, N.Z., Caveney, N., Edgar, L., Newman, J.W., Cogo-Moreira, H., Swardfager, W. 2025. Type 2 diabetes mellitus, cognitive performance, and incident dementia; identifying mediating pathways and biomarkers from the plasma proteome. Journal of Neurochemistry. 169(12). Article e70306. https://doi.org/10.1111/jnc.70306.
DOI: https://doi.org/10.1111/jnc.70306

Interpretive Summary: Type 2 diabetes is associated with poorer cognitive performance and increased dementia risk, but we do not understand why. Using a large set of samples from the United Kingdom Biobank we confirmed that diabetes was associated with poor attention, processing speed, and a higher risk of dementia over 15 years. An analysis or almost 3,000 proteins in the blood identified a subset influenced that mediated or moderated the association of diabetes with cognitive functions and implicated biochemical pathways involved in inflammation and cholesterol metabolism as responsible, and may indicate novel targets to slow the cognitive decline and dementia associated with Type 2 diabetes.

Technical Abstract: Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk. Pathophysiological mechanisms are not fully understood. In the UK Biobank (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 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]). This study suggests potential targets to mitigate cognitive decline and dementia risk in T2DM.