Defining the Relationships Among Comorbid Posttraumatic Stress Disorder and Obstructive Sleep Apnea and MRI Measures of Glymphatic Function and Plasma AD Biomarkers in OEF/OIF/OND Veterans

Posttraumatic stress disorder (PTSD) is a highly prevalent and often chronically disabling disorder among Veterans. Sleep impairment with frightening trauma combat nightmares and distressed awakenings accompanied by both increased peripheral and brain noradrenergic signaling are common features of PTSD in Veterans. In addition to the adverse of impacts of PTSD on Veterans’ sense of well-being and ability to function, epidemiologic studies demonstrate that PTSD is a risk factor for development of all cause dementia and Alzheimer’s disease (AD). Another disorder highly prevalent among Veterans and particularly among Veterans with PTSD is obstructive sleep apnea (OSA). Epidemiologic studies demonstrate that OSA also is a risk factor for dementia and AD. Thus, Veterans with both PTSD and OSA are likely at particularly high risk for later life dementia and AD. A potential mechanism by which both PTSD and OSA increase the risk for AD is impairment of the brain glymphatic system. The glymphatic system clears the brain of metabolic waste products and neurotoxic proteins, including amyloid beta Abeta42 and tau, the pathological hallmarks of AD. The brain glymphatic system is active during normal sleep and relatively quiescent during wakefulness. In addition, the glymphatic system is suppressed by noradrenergic signaling. Impaired sleep and elevated noradrenergic signaling (particularly at night) are important features of both PTSD and OSA. We hypothesize that PTSD and OSA impair glymphatic function and this impairment is greatest in Veterans with both conditions. We also hypothesize that plasma biomarker signature of AD will be greatest in Veterans with both PTSD and OSA. Our preliminary findings support these hypotheses. In a cohort of Veterans of Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) who met diagnostic criteria for PTSD, 80% reported a moderate-to-high burden of trauma nightmares and sleep disturbance. In these Veterans, poor sleep was associated with both increased cerebrospinal fluid (CSF) norepinephrine (NE) -- consistent with increased brain noradrenergic signaling -- and lower CSF amyloid-beta42 (Abeta42) -- an early biomarker for AD. We will explore this hypothesis through a mechanistic translational study. Participants will be 100 middle- aged OEF/OIF/OND-deployed Veterans: 70 with a diagnosis of PTSD with and without OSA and 30 deployed control Veterans with neither PTSD nor OSA. Because of our preliminary data establishing a relationship among impaired sleep, increased brain noradrenergic signaling, and CSF Abeta42 in OEF/OIF/OND Veterans, we will select what we consider to be the “noradrenergic subtype” of PTSD, characterized by moderate-to- extreme distressing dreams and sleep disruption assessed by the Clinician-Administered PTSD Scale For DSM-5. Recent improvements in biofluid biomarkers have allowed measurement of AD biomarkers in plasma rather than CSF. Plasma Abeta42, Abeta40, and phosphorylated tau (ptau) 217 will be measured on the state- of-the-art Lumipulse 1200G platform. Specific Aim 1. Define the effect of PTSD and OSA on glymphatic function in Veterans. Specific Aim 2. Define the effect of PTSD and OSA on AD-related biomarkers and cognitive function. Exploratory Aim. To determine if CPAP therapy improves glymphatic function and plasma AD biomarkers in Veterans with PTSD and OSA. The Research Project as well as the Mentorship and Career Plans in this application will prepare the candidate, Dr. Cho, a sleep medicine physician, to pursue an independent research career in the VA focusing on the effects of PTSD and OSA on Veterans’ health and pursuing novel strategies to reduce risk of AD. Project Number: 1IK2RX005079-01A2 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Yeilim Cho | Institution: VA PUGET SOUND HEALTHCARE SYSTEM, SEATTLE, WA | Activity Code: IK2 | Study Section: Brain Health and Injury[RRD1] View on NIH RePORTER: https://reporter.nih.gov/project-details/11112257