Relationships between locus coeruleus structural integrity and nocturnal awakenings in the context of AD biomarkers: A 7T MRI study

Abstract Background The brainstem locus coeruleus (LC) may constitute the intersection of the initial pathophysiological and clinical phenotypes of Alzheimer’s disease (AD). Tau protein accumulation starts early in the LC and sleep‐wake disruption occurs in early stages of AD, potentially reflecting arousal dysregulation in wake‐promoting neurons of the LC. Here, we sought to investigate whether LC structural integrity could be related to subjective sleep‐wake measures in the context of AD biomarkers. Method We used an in‐house developed LC‐specific MRI sequence at 7T in 72 cognitively normal older participants (mean age = 65.2 ± 8.2y; 37 women), and we identified sub‐portions of the LC using intensity‐based cluster analyses. Participants’ reports on habitual sleep quality and nocturnal awakenings were collected. In addition, blood‐based biomarker of total tau was measured, and APOE genotype was determined. Result Two distinct LC segments were identified, with one covering the middle‐to‐caudal LC and displaying lower intensity compared to the middle‐to‐rostral cluster ( t (70) = ‐4.40, p < .0001). Generalized linear mixed models adjusted for age, sex, depression, and APOE status showed that subjective sleep quality was not related to any LC integrity measures. However, we found that lower MRI signal intensity within the middle‐to‐caudal LC, but not in the middle‐to‐rostral LC, was associated with a higher number of self‐reported nocturnal awakenings (F 1,63 = 4.89, p = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau (F 1,61 = 4.23, 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 normal older individuals. In addition, they further emphasize the role of the LC in the arousal‐ascending system as an important neurobiological correlate of sleep‐wake regulation, and hold promise for the identification of at‐risk populations for preventive interventions.