Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome

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.