Circulating inflammatory proteins predict dementia risk, are linked to structural brain changes and reveal risk mediation pathways

Introduction Systemic Inflammation has been identified key factor in neurodegeneration but the value of circulating inflammatory proteins in dementia risk prediction and their causal role has not been elucidated. Methods We leveraged proteomics data from 43,685 UK Biobank participants to investigate associations between 728 Olink inflammatory proteins and incident dementia using Cox proportional-hazard (Cox-PH) models. We used Cox-PH with LASSO regularisation to calculate a sparse signature of inflammatory proteins (ProSig) predicting incident dementia. Linear regressions assessed the association between ProSig and individual proteins with brain image-derived phenotypes (IDPs) and Brain Age in participants with available neuroimaging data (n = 4,106). Formal mediation analyses investigated whether inflammatory proteins mediated associations between genetic and modifiable risk factors and dementia outcomes. Mendelian randomization (MR) tested the causal relationship between inflammatory proteins and dementia outcomes. Results 218 inflammatory proteins were individually associated with incident dementia in Cox PH models (pFDR < 0.05). A 20-protein signature significantly improved the prediction of incident dementia beyond known risk factors. TNFRSF11B, a protein linked to vascular damage, was associated with both incident dementia and reduced hippocampal volume. Two proteins, sFRP4 and MEPE, were linked to reduced Brain Age with sFRP4 being also protective against dementia. Mediation analyses suggested that TNFRSF11B, APOE, and C7 partially mediated the effects of modifiable risk factors on dementia. MR analyses highlighted protective causal roles for TNFSF13 and IL17D. Conclusions By triangulating evidence, this study shows that inflammatory proteins improve dementia risk prediction and play heterogeneous causal roles in dementia pathophysiology.