Pathophysiological Study of Alzheimer's Disease and Related Dementia

National Institute On Aging

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Abstract

Disturbances in the sleep–wake cycle and circadian rhythms are common and debilitating symptoms of Alzheimer’s disease (AD), yet effective treatments are lacking. Emerging evidence suggests that physical activity may benefit brain health, but its effects on sleep regulation in AD remain poorly understood. This project investigates the impact of voluntary wheel running (VWR) exercise on sleep architecture, circadian clock gene expression, cognitive function, and neuropathology in a well-established transgenic mouse model of AD (APPSWE/PS1dE9). Over a two-month intervention, VWR exercise markedly improved behavioral circadian rhythm disturbances and increased rapid eye movement (REM) sleep by 89%. In the suprachiasmatic nucleus (SCN), the brain’s master circadian clock, VWR altered the expression of key clock genes (Bmal1, Rorα, Rev-erbα) and reduced tau phosphorylation and axonal damage in γ-aminobutyric acid (GABA)ergic neurons. In the hypothalamus, levels of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β) were decreased. Furthermore, in the hippocampus and cortex, VWR reduced neuroinflammation, amyloid beta (Aβ) deposition, and phospho-tau accumulation, while improving cognitive performance. These findings provide compelling preclinical evidence that regular voluntary exercise can ameliorate sleep–wake disturbances and mitigate neuropathology in AD. By identifying molecular and circuit-level mechanisms linking exercise to improved circadian and cognitive function, this work advances our understanding of non-pharmacological interventions for AD and related dementias, with potential to inform future therapeutic strategies in human patients.