Zona incerta circuits in cognition and the regulation of sleep and wakefulness: potential relevance to Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and prominent disturbances in sleep and wakefulness, reflecting dysfunction across distributed neural networks. The zona incerta (ZI) is a highly heterogeneous subthalamic structure whose organization is defined by spatial location, molecular identity, neurochemical phenotype, and circuit connectivity. Recent studies demonstrate that distinct ZI cell populations and projections contribute to memory processing, novelty seeking, cortical plasticity, sleep promotion, rapid eye movement (REM) sleep, transitions to wakefulness, and sleep homeostasis. Together, these findings suggest that the ZI is better viewed as a state-dependent subcortical regulatory platform than as a unitary cognitive or sleep center. Emerging pathological evidence further raises the possibility that the ZI may be relevant to neurodegeneration. Amyloid-β deposition has been reported in the ZI of 5xFAD transgenic mice, while experimental tau propagation, human tauopathies other than AD, and studies of other neurodegenerative disorders indicate potential cellular and circuit vulnerability. However, direct evidence from human AD remains lacking, and no study has established a causal pathway from AD pathology to selective ZI dysfunction and subsequent cognitive or sleep impairment. We therefore propose two testable models in which the ZI contributes to AD phenotypes either as a shared circuit node or through parallel, selectively vulnerable functional modules.