Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.

Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism.

Design, setting, and participants: This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses.

Main outcomes and measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes.

Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms.

Conclusions and relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk.

Trial registration: ClinicalTrials.gov Identifier: NCT02977819.

Figure 1.. Flow Diagram of the Inclusion Process

APOE indicates apolipoprotein E; CPAP, continuous positive airway pressure; FDG, ¹⁸F-fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography; SDB, sleep-disordered breathing.

Figure 2.. Neuroimaging Pattern of the Significant Differences Between Participants With vs Without Sleep-Disordered Breathing in Amyloid Deposition, Gray Matter Volume, Perfusion, and Glucose Metabolism

Results of the voxelwise analyses of covariance exhibiting between-group differences in amyloid deposition (A), gray matter (GM) volume (B), perfusion (C), and glucose metabolism (D), using magnetic resonance imaging and partial volume effects–corrected positron emission tomography data. Analyses were adjusted for age, sex, education, body mass index, sleep medication use, and APOE4 status. Results were obtained at a P < .005 (uncorrected) threshold, and only clusters surviving a familywise error–cluster-level correction are reported. APOE indicates apolipoprotein E; SDB−, negative for sleep-disordered breathing; SDB+, positive for sleep-disordered breathing.

Figure 3.. Overlap of Sleep-Disordered Breathing–Associated Brain Changes Across Neuroimaging Modalities

Representation of the overlap between sleep-disordered breathing–associated patterns of greater perfusion (blue) and amyloid deposition (pink), obtained at a P < .005 (uncorrected) threshold combined with a familywise error–cluster-level correction.