Locus coeruleus activity is related to sleep and 24-h rest-activity rhythms in the context of plasma Alzheimer’s disease markers: a 7T MRI study of older individuals

The brainstem locus coeruleus (LC), an early site of tau pathology and a key regulator of arousal and sleep-wake dynamics, has emerged as a potential neurobiological substrate underlying the relationship between sleep-wake disturbances and AD pathogenesis. Yet, the interplay between LC functional metrics, sleep-wake regulation, and early AD pathology remains poorly understood. Here, we investigated whether plasma AD-related biomarkers moderate the relationship between LC activity and objective sleep-wake measures in asymptomatic older individuals. Fifty-five cognitively unimpaired older adults underwent 10 days of actigraphy, blood drawing, and a daytime 7T MRI protocol including dedicated LC imaging and an affective visual task comprising high-arousing and low-arousing images. Arousal-based LC activity was determined by the high-versus-low-arousal (H > L) contrast. A subset of individuals ( n = 30) also performed three nights of at-home sleep EEG recordings. Plasma AD-related biomarkers included glial fibrillary acidic protein (GFAP) and tau phosphorylated at threonine 181 (ptau 181 ), 217 (ptau 217 ) and 231 (ptau 231 ). Interaction models adjusted for age, sex, BMI and device wear duration showed that, at higher levels of GFAP and several ptau markers, lower LC activation to the emotional stimuli during the task was related to shorter actigraphy-derived sleep duration, lower sleep efficiency (SE), and higher wake after sleep onset (WASO%). We observed similar patterns using 24-h rest–activity rhythm, such that, at higher burden of GFAP and several ptau markers, lower H > L LC was associated with higher intradaily variability (IV) and lower interdaily stability (IS). Examining sleep architecture, we showed that participants with lower LC activation to emotional stimuli during the task and higher burden of different ptau markers exhibited a higher proportion of time spent in N2 sleep stage, along with lower time spent in N3 sleep stage. Lower daytime task-related LC activity was related to shorter, lighter, and more fragmented sleep as well as to disruption of circadian rest-activity patterns in the presence of biomarker evidence of early AD pathology in asymptomatic older individuals. These findings suggest that LC dysfunction may aggravate, while preserved LC function may protect against early AD-related sleep-wake disturbances.