Microstructural assessment of the locus coeruleus-entorhinal cortex pathway and association with ATN markers in cognitive impairment

Alzheimers Dement. 2025 Apr;21(4):e70126. doi: 10.1002/alz.70126.

ABSTRACT

INTRODUCTION: Whether Alzheimer’s disease pathology involves white matter pathways connecting the locus coeruleus (LC) to the entorhinal cortex (EC) is unclear. In this cross-sectional observational study, we investigated the microstructural integrity of the LC-EC pathway in relation to amyloid, tau, and neurodegeneration (ATN) biomarkers along the cognitive spectrum from normal cognition to dementia.

METHODS: One hundred twenty-four participants underwent clinical assessment, diffusion-weighted imaging, structural magnetic resonance imaging (N), amyloid (A), and tau (T) positron emission tomography. Diffusivity indices were assessed in the LC-EC tract using a probabilistic atlas, and linear models were used to assess associations with ATN markers and cognition.

RESULTS: Differences in LC-EC microstructural parameters were observed in participants with Braak stage > I versus Braak 0 (p < 0.020), N+ versus N- (p < 0.001), and cognitively impaired versus unimpaired (p < 0.019). LC-EC mean diffusivity was associated with Mini-Mental State Examination score even after accounting for ATN markers (p = 0.015).

DISCUSSION: Our results suggest that LC-EC diffusivity provides complementary information over ATN biomarkers in explaining cognitive impairment.

HIGHLIGHTS: Locus coeruleus-entorhinal cortex (LC-EC) tract microstructure is associated with tau and especially neurodegeneration markers. LC-EC tract microstructure is more sensitive to tau pathology and neurodegeneration than tracts commonly affected in Alzheimer’s disease. LC-EC diffusivity measures provide complementary information over amyloid, tau, and neurodegeneration (ATN) biomarkers.

PMID:40289861 | DOI:10.1002/alz.70126