Behavioral and brain-wide neural signatures of sundowning in Alzheimer’s disease

Sundowning, a common yet poorly understood neuropsychiatric syndrome in Alzheimer’s disease (AD), manifests as evening-specific increases in agitation, confusion, and anxiety. Despite its prevalence and contribution to patient distress, its neural mechanisms remain elusive. Here, we establish a preclinical model of sundowning by characterizing sleep-wake, behavioral, and network-level alterations in an AD mouse model. Aged AD mice exhibit disrupted sleep-wake patterns and reduced slow-wave sleep. Behavioral and pose-tracking analyses revealed motor agitation and a distinct sundowning-like behavioral fingerprint selectively at Sundown. The suprachiasmatic nucleus (SCN) showed disruptions in time-of-day-dependent activation of vasopressin-expressing cells and brain-wide activity-dependent tagging identified hyperconnectivity amongst sensorimotor regions in AD mice at Sundown. Resting-state fMRI data from the Alzheimer’s Disease Neuroimaging Initiative revealed analogous Salience Network alterations in AD subjects. Overall, these cross-species findings define a systems-level framework for sundowning and highlight regions that may be targeted to alleviate a debilitating symptom of AD.