Abstract
BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and functional loss in older adults. Obstructive sleep apnea (OSA) is common in older adults, can increase cerebrovascular disease risk, and is linked to medial temporal lobe (MTL) degeneration and cognitive impairment. However, the interaction between OSA features and CSVD burden and their combined effect on MTL structure and function are not well understood. This study tested the hypothesis that CSVD burden is a candidate mechanism linking OSA to MTL degeneration and impaired memory in older adults. METHODS: Cognitively unimpaired older adults from the Biomarker Exploration in Aging, Cognition, and Neurodegeneration cohort were recruited for an observational, in-lab overnight polysomnography (PSG) study with emotional mnemonic discrimination ability assessed before and after sleep. Participants had no neurologic or psychiatric disorders and were not on sleep-affecting medications. PSG-derived OSA variables included apnea-hypopnea index (AHI), total arousal index, and minimum SpO(2). MRI was used to assess global and lobar white matter hyperintensity (WMH) volumes and MTL structure (hippocampal volume; entorhinal cortex [ERC] thickness) at an earlier time point. Regressions were implemented while adjusting for age, sex, and concurrent use of antihyperlipidemic and/or antihypertensive medication. Minimum SpO(2) was transformed into a Hypoxemia Severity Index for normality, in which lower SpO(2) values indicated more severe hypoxemia. RESULTS: Thirty-seven older adults were included in the study (age 72.5 ± 5.6 years, 23 women, AHI = 13.8 ± 18.0 [range 0-80]). Hypoxemia measures significantly predicted global WMH volume (b(minSpO2) = 0.141 [0.001-0.282], b(duration <90%) = 0.008 [0.000-0.016]). This relationship was driven by hypoxemia severity during REM sleep (b(REMminSpO2) = 0.143 [0.003-0.284]), which also predicted frontal (b(REMminSpO2) = 0.101 [0.004-0.198]) and parietal (b(REMminSpO2) = 0.121 [0.024-0.219]) WMH burden. Greater frontal WMH burden indirectly mediated the relationship between REM sleep hypoxemia and ERC thickness (indirect effect = -0.043, 95% CI -0.1174 to -0.00015). Reduced ERC thickness was, in turn, associated with worse overnight mnemonic discrimination ability (b(leftERCthickness) = 0.112 [0.014-0.211]). DISCUSSION: These findings identify CSVD as a candidate mechanism linking OSA-related hypoxemia to MTL degeneration and impaired sleep-dependent memory in older adults, specifically implicating hypoxic events during REM sleep.