Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer’s disease plasma biomarkers: a 7T MRI study

Background The brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer's disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals. Methods Seventy-two cognitively unimpaired older individuals aged 50-85 years (mean age = 65.2 [+ or -] 8.2 years, 37 women, 21 APOE [epsilon]4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau.sub.181, A[beta].sub.40, and A[beta].sub.42 were measured using single-molecule array technology. Results Intensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t.sub.70 = -5.12, p < 0.0001). After correction for age, sex, depression, and APOE status, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F.sub.1,63 = 6.73, p.sub.FDR = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F.sub.1,61 = 4.26, p = 0.04). Conclusion Our findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions. Keywords: Alzheimer's disease, Locus coeruleus, Ultra-high field neuroimaging, Subjective sleep metrics, Blood-based Alzheimer's disease biomarkers