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

May 4, 2026Research square

Behavior and brain activity patterns linked to sundowning in Alzheimer's disease

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Aged Alzheimer's disease mice show disrupted sleep-wake patterns and increased agitation specifically in the evening.

Sundowning is associated with heightened agitation, confusion, and anxiety in Alzheimer's disease.
Behavioral analyses in AD mice revealed a unique pattern of agitation occurring at Sundown.
Alterations in the suprachiasmatic nucleus were observed, indicating disrupted activation of specific cells related to time of day.
Increased connectivity among sensorimotor regions was identified in AD mice during the evening.
Resting-state fMRI data from human subjects with Alzheimer's disease showed similar changes in the Salience Network.

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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.

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

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