A new hope: locus coeruleus-norepinephrine system at the nexus of neuropsychiatric symptoms

The earliest stages of Alzheimer's disease (AD) are frequently characterized by neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, compulsivity, appetite dysregulation, and sleep disturbances, often preceding measurable cognitive decline. Evidence from clinical and animal studies implicates hyperactivity of the locus coeruleus-norepinephrine (LC-NE) system as a mechanistic driver of these behaviors. Here, we review noradrenergic circuits that can potentially underlie psychiatric disturbances to identify therapeutic targets for preventing and delaying onset of AD. Given that this system influences attention, arousal, mood, and stress responses, LC-NE hyperactivity across circuitry involving amygdala, thalamus, hypothalamus, anterior cingulate cortex, prefrontal cortex, and olfactory areas can contribute to NPS features in early AD. Advances in neuroimaging and physiological measures of noradrenergic function have enabled in vivo tracking of LC integrity and NE transmission, offering the opportunity to detect LC-NE dysfunction early in disease progression and potentially implement targeted pharmacologic and neuromodulatory interventions to restore optimal LC-NE tone. Overall, dissection of LC-NE circuitry and its clinical translation hold promise for developing biomarker-driven, stage-specific interventions to reduce NPS burden and enhance the efficacy of disease-modifying therapies in AD.