Exploring the Overlooked Role of Orexin in Alzheimer Disease and Sleep Dysfunction: Lea Grinberg, MD, PhD

The relationship between sleep and Alzheimer disease (AD) is increasingly recognized as bidirectional: disrupted sleep can contribute to the development and progression of AD, while AD pathology itself can impair sleep-wake regulation. Sleep plays a critical role in clearing neurotoxic waste products, including beta-amyloid and tau, through the glymphatic system, a process that is most active during slow-wave sleep.

The 2025 SLEEP Annual Meeting, held June 8-11, in Seattle, Washington, brought together the latest in sleep-related research, including discussions about the interplay between sleep and neurodegenerative disorders like AD. One session, led by chair Thomas Neylan, MD, covered orexin/hypocretin neuron loss and sleep disturbances in aging and early stages of AD. Considered a hot topic in the field, the discussion featured presentations from Luis de Lecea, PhD; Christine Walsh, PhD, and Lea Grinberg, MD, PhD.

Grinberg, a neuropathologist who recently started working at Mayo Clinic Florida, sat down with NeurologyLive^® to give insights on her talk and why it was a topic of interest. In the interview, she shared findings from her lab’s work that revealed that tau accumulation begins in subcortical wake-promoting nuclei-predating entorhinal cortex involvement and even neuronal loss in the locus coeruleus. This neuron loss correlates with sleep-wake disturbances, offering a potential early biomarker for disease onset. Above all, Grinberg emphasized that understanding these molecular and structural disruptions opens the door to repurposing existing neuromodulatory drugs to treat sleep dysfunction and potentially delay AD progression.