Peripheral TARC (CCL17) Levels Track Widespread Microstructural Vulnerability in Cognitively Unimpaired Older African...

Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans.

Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure.

Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions.

These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations.