DNA Methylation Signatures of Systemic Inflammation Are Associated With Brain Volume, Cognitive Trajectories, and...

Area of Science:

• Neuroscience
• Epigenetics
• Inflammation Biology

Background:

• C-reactive protein (CRP) and growth differentiation factor 15 (GDF15) are established inflammation markers linked to brain health.
• Plasma-based markers may not fully capture chronic inflammatory exposure, necessitating exploration of more stable measures like DNA methylation (DNAm).

Purpose of the Study:

• To investigate whether DNAm measures of CRP and GDF15 serve as robust predictors of brain aging and neurodegeneration.
• To compare the predictive power of DNAm versus plasma markers for brain health and dementia risk.

Main Methods:

• Utilized data from the Baltimore Longitudinal Study of Aging (BLSA) including DNAm, plasma, neuroimaging, and cognitive data.
• Employed proteome-wide analysis for biological characterization and latent growth curve models for longitudinal associations with brain volumes and cognition.
• Validated findings in two external cohorts assessing dementia risk.

Main Results:

• DNAm CRP and GDF15 exhibited proteomic signatures indicative of systemic immune activation.
• Elevated DNAm CRP and GDF15 were associated with reduced brain volume and accelerated atrophy in specific regions.
• DNAm CRP demonstrated stronger associations with brain volume, cognitive trajectories, and dementia risk than plasma CRP.

Conclusions:

• Epigenetic signatures of CRP and GDF15 reflect immune and inflammation pathway activation.
• DNAm measures, particularly DNAm CRP, are strongly associated with accelerated brain atrophy, cognitive decline, and long-term dementia risk.
• DNAm offers a more stable and predictive epigenetic measure of inflammation's impact on brain aging compared to plasma markers.