Vulnerability of the locus coeruleus–entorhinal cortex white matter tract in autosomal dominant Alzheimer's disease

INTRODUCTION: Locus coeruleus (LC) structural integrity declines early in sporadic and autosomal dominant Alzheimer's disease (AD). We examined LC-entorhinal cortex (LC-EC) tract integrity and its association with amyloid and tau pathology and memory in autosomal dominant AD (ADAD). METHODS: F-FTP] positron emission tomography PET), and memory in PSEN1-E280A mutation carriers (n = 30) and non-carriers (n = 33). RESULTS: LC-EC tract integrity was lower in females and older individuals in both non-carriers and carriers. In mutation carriers, lower tract integrity was associated with higher entorhinal tau and poorer memory, with tau and amyloid mediating the tract-memory relationship in the entire sample but not in unimpaired carriers. DISCUSSION: These findings highlight the LC-EC tract as an early disease vulnerability marker in ADAD, with tract disruption associated with memory decline across disease stages, a relationship further mediated by entorhinal tau pathology as disease progresses.