Astrocyte reactivity modifies the effects of locus coeruleus norepinephrine‐related dysfunction on tau and its impact on cognition

INTRODUCTION Animal models demonstrated that pharmacologically‐induced lesioning of the locus coeruleus (LC), the brain's primary source of norepinephrine, triggered astrocyte reactivity, exacerbating Alzheimer's disease (AD) pathology and cognitive deficits. We examined whether astrocyte reactivity modulates the relationship between LC dysfunction, tau pathology, and cognitive decline in humans. METHODS We combined ultra‐high‐field LC functional imaging during an affective task with plasma biomarkers of glial fibrillary acidic protein (GFAP) and hyperphosphorylated tau (p‐tau), and longitudinal cognitive data from 78 asymptomatic individuals. Associations between LC activity and norepinephrine transporter‐enriched LC functional connectivity (LCFC) with p‐tau, GFAP, and cognitive decline were examined. RESULTS Lower LC activity and LCFC were related to elevated plasma p‐tau 217 , particularly at elevated GFAP. Lower LC FC was also associated with cognitive decline in individuals with elevated plasma p‐tau 217 and GFAP. DISCUSSION LC–norepinephrine system dysfunction may contribute to emerging tau pathology and cognitive decline, with astrocytes playing a critical gating role.