Noradrenergic Locus Coeruleus Hyperactivity Alters Attention in Cognitively Healthy Older Adults

Abstract Animal models of Alzheimer’s disease have shown that neuropathology in the locus coeruleus (LC) leads to increased neuronal firing, while human studies demonstrate that age-related dysregulation of the LC-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyperactivity. In this study, we tested the hypothesis that cognitively healthy older adults sustain tonic LC hyperactivity, by acquiring electrophysiological, pupillometric, and behavioral measures during a passive and active auditory oddball paradigm. We capitalized on the LC-NA system’s role in arousal regulation and manipulated state arousal using the threat of electric shock. We hypothesized that if older adults maintain elevated LC activity compared with young adults, task-evoked noradrenergic responses would be less responsive to arousal in older adults. Consistent with this hypothesis, arousal elicited weaker behavioral responses, pupil dilation responses, and P300 event-related potentials in older adults compared with young adults. Linear mixed models revealed an arousal by modality interaction and revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors between both age groups. Collectively, these findings support the hypothesis that aging is associated with tonic LC-NA system hyperactivity in humans, with downstream consequences for mechanisms of attentional control. These multimodal findings underscore the potential of non-invasive physiological markers to assess LC-NA system function throughout aging and identify individuals at elevated risk for neurodegenerative progression prior to the emergence of clinical biomarkers.