UC Irvine

Alzheimer's disease is a progressive neurodegenerative disorder with no current effective cure and the leading cause of dementia worldwide. Episodic memory decline is among the earliest cognitive symptoms of Alzheimer's disease and is closely linked to dysfunction of medial temporal lobe (MTL) circuits. Emerging evidence suggests that sleep physiology and cerebrovascular health may play important roles in maintaining MTL integrity and supporting sleep-dependent memory processes. However, the mechanisms through which sleep disturbances, vascular pathology, and MTL integrity interact to influence memory function in aging remain poorly understood. To address these gaps, a series of studies were conducted. In Chapter 2, longitudinal changes in non-rapid eye movement (NREM) sleep oscillatory dynamics critical for memory consolidation processes during sleep were examined in cognitively unimpaired middle-aged and older adults at risk for Alzheimer’s disease, using high-density electroencephalography across two timepoints separated by approximately 2.5 years. Longitudinal changes of local slow wave activity, sleep spindle expression, and slow oscillation-fast sigma coupling were assessed to determine how sleep microarchitecture changes over time and whether these changes relate to markers of synaptic integrity and episodic memory trajectories. In Chapter 3, the interaction between obstructive sleep apnea (OSA) and cerebrovascular pathology was examined as a potential mechanism linking sleep-disordered breathing to structural and functional changes of the MTL. Polysomnography-derived indices of OSA severity were combined with magnetic resonance imaging measures of white matter hyperintensity burden and MTL structure to test whether cerebrovascular disease mediates the relationship between sleep-related hypoxemia and sleep-dependent mnemonic discrimination performance. Chapter 4 presents a conceptual framework proposing that rapid eye movement (REM) sleep-related respiratory events represent a critical window through which sleep-disordered breathing may amplify vascular contributions to Alzheimer's disease risk, particularly through increased vulnerability of the MTL to vascular insult. Finally, in Chapter 5, diffusion magnetic resonance imaging and polysomnography were used to investigate whether microstructural alterations in the stria terminalis, a major amygdala efferent pathway vulnerable to cerebrovascular pathology, contribute to age-related differences in sleep-dependent emotional memory retention. Together, these studies provide novel insights into how sleep physiology, cerebrovascular health, and MTL integrity interact to influence sleep-dependent memory in aging. Findings from this dissertation highlight sleep as a potential mechanistic pathway linking vascular and synaptic processes to cognitive decline and may inform future interventions aimed at preserving memory and reducing Alzheimer's disease risk.