Locus coeruleus‐entorhinal cortex tract integrity is linked to plasma tau and glial fibrillary acidic protein

Abstract INTRODUCTION Pretangle tau inclusions from the locus coeruleus (LC) are hypothesized to propagate to the entorhinal cortex (EC) via neuron‐to‐neuron transmission along its projections. The lower integrity of the LC‐EC pathway accompanying Alzheimer's disease (AD) pathology is supported by post mortem studies, but in vivo evidence remains limited. METHODS We associated diffusion‐weighted 7T magnetic resonance imaging (MRI) metrics of microstructural integrity within the LC‐EC tract to plasma AD‐related biomarkers in a cohort of 47 cognitively unimpaired adults. RESULTS Worse overall and local LC‐EC integrity, indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), was related to elevated concentrations of plasma phosphorylated tau 181 (p‐tau181), p‐tau217, and glial fibrillary acidic protein (GFAP). A higher orientation dispersion index (ODI) within the LC‐EC tract was linked to elevated plasma p‐tau181 and p‐tau231 levels. DISCUSSION The lower integrity of the LC‐EC pathway may serve as a key indicator of the earliest AD‐related pathophysiological processes to improve detection of at‐risk individuals. Highlights Standard DTI model metrics in the LC‐ EC tract are linked to elevated plasma p‐tau and GFAP. A higher ODI in the voxels containing the LC‐EC tract is related to elevated plasma p‐tau. LC‐EC integrity links to AD‐related biomarkers show topographic specificity. Lower LC‐EC integrity may be a key indicator of the earliest AD‐related pathology.