Circulating inflammatory proteins predict dementia risk, and are linked to structural brain changes and modifiable...

Area of Science:

• Neuroscience
• Proteomics
• Genetics

Background:

• Systemic inflammation is implicated in neurodegeneration.
• The role of circulating inflammatory proteins in dementia risk and causality requires elucidation.

Purpose of the Study:

• Investigate associations between inflammatory proteins and incident dementia.
• Develop a predictive model for dementia risk using inflammatory proteins.
• Explore the causal relationships and mediating roles of inflammatory proteins in dementia.

Main Methods:

• Utilized proteomic data from 43,685 UK Biobank participants.
• Employed Cox proportional-hazards models and LASSO regularization for predictive signature development.
• Conducted mediation analyses and Mendelian randomization to assess causality and mediating effects.

Main Results:

• 218 inflammatory proteins associated with incident dementia; a 20-protein signature improved prediction.
• TNFRSF11B linked to dementia and reduced hippocampal volume; sFRP4 and MEPE associated with reduced Brain Age.
• Evidence suggests inflammatory proteins mediate risk factor associations and some have protective causal effects.

Conclusions:

• Inflammatory proteins are valuable for improving dementia risk prediction.
• These proteins exhibit heterogeneous roles in dementia pathophysiology.