0503 Physiologic Burdens of Sleep Apnea and Risk of Parkinson’s Disease in a Clinical Cohort of Over 4000 Patients

Abstract Introduction Obstructive sleep apnea has been associated with increased risk of Parkinson’s disease (PD), yet findings remain inconsistent. Preclinical studies suggest hypoxia may have protective effects on PD, and higher apnea-hypopnea index (AHI) appeared protective in our recent work. To clarify underlying mechanisms, we examined how distinct physiologic burdens of sleep apnea, including hypoxic burden (HB), ventilatory burden (VB), and arousal burden (AB), relate to subsequent PD risk. Methods We examined adults ≥50 years who underwent in-laboratory polysomnography (PSG) at Massachusetts General Hospital (2010–2020) from the Human Sleep Project, excluding those with supplemental oxygen or pre-existing PD. Incident PD was defined as ≥2 PD ICD codes, ≥2 PD-related medication use, and no exclusionary neurological diseases. HB quantified cumulative oxygen desaturation area divided by total sleep time; VB quantified the proportion of breaths 50% normalized amplitude; AB quantified total arousal duration relative to total sleep time. Associations with PD risk were estimated using Cox regression, adjusting for demographics, body mass index, smoking, cardiovascular and pulmonary comorbidities, REM sleep behavior disorder, and sleep medication. Additional analyses assessed each burden separately during REM and NREM sleep. Secondary analyses further adjusted for AHI and accounted for competing risk of death. Results Among 4,100 individuals (age 62.3 ± 8.7 years, 52.7% female, 24.2% non-White) followed for 9.8 ± 3.3 years, 100 (2.4%) developed PD. Higher HB was associated with lower PD risk (Q2 HR=0.350, 95% CI: 0.181–0.675, P=0.003; Q3 HR=0.357, 95% CI: 0.191–0.669, P=0.002; Q4 HR=0.571, 95% CI: 0.332–0.982, P=0.046; all reference: Q1). Higher AB was also associated with lower PD risk (Q3 HR=0.526, 95% CI: 0.294–0.940, P=0.033; Q4 HR=0.497, 95% CI: 0.280–0.883, P=0.020). VB showed no significant association. Notably, HB and AB during REM, but not NREM, were associated with lower risks. Findings remained robust with secondary analyses. Conclusion Among 4000 patients who underwent in-lab PSG, higher hypoxic and arousal burdens were associated with lower risks of PD, potentially reflecting neuroprotective hypoxic preconditioning or altered sleep propensity due to degeneration of wake-promoting neurons in prodromal PD. Future studies should clarify the complex sleep apnea-PD relationship and delineate apnea phenotypes that map onto distinct physiological pathways. Support (if any) NIA (R21AG085495)