Associations of obstructive sleep apnea with A/T/N biomarkers, neuroimaging abnormalities, neurodegenerative progression, and CPAP-related changes in Alzheimer's disease.

BACKGROUND

Obstructive sleep apnea (OSA) has been increasingly linked to cognitive impairment and dementia, yet its relationship with core Alzheimer's disease (AD) pathology, multimodal brain injury, longitudinal neurodegenerative progression, and potential treatment responsiveness remains incompletely understood.

METHODS

Cross-sectional analyses compared amyloid/tau/neurodegeneration (A/T/N) biomarkers and multimodal neuroimaging measures between groups, including cerebrospinal fluid (CSF) biomarker quantification, amyloid positron emission tomography (PET), structural MRI, white matter imaging, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume, the latter two used as indirect imaging markers reflecting potential alterations in glymphatic-related fluid transport and waste-clearance pathways. Among OSA participants who initiated continuous positive airway pressure (CPAP) therapy, changes over the approximately 6-month follow-up period were compared according to adherence status.

RESULTS

Compared with patients without OSA, those with OSA showed a more adverse A/T/N biomarker profile, including lower CSF Aβ42 (528.19 ± 147.83 vs 612.37 ± 158.46 pg/mL), lower CSF Aβ42/40 ratio (0.064 ± 0.013 vs 0.071 ± 0.014), higher amyloid PET SUVR (1.38 ± 0.21 vs 1.24 ± 0.18), higher CSF p-tau181 (74.92 ± 26.15 vs 63.48 ± 21.37 pg/mL), higher plasma NfL (31.79 ± 13.27 vs 24.68 ± 10.42 pg/mL), and higher plasma GFAP (233.47 ± 104.26 vs 196.54 ± 82.71 pg/mL). Neuroimaging analyses further showed smaller hippocampal volume, greater white matter injury, a lower DTI-ALPS index (1.27 ± 0.18 vs 1.43 ± 0.19), and a larger choroid plexus volume (3291.73 ± 768.61 vs 2814.56 ± 712.48 mm3) in the OSA group. Longitudinally, OSA was associated with faster annual increases in NfL (2.37 vs 0.72 pg/mL/year) and GFAP (15.19 vs 4.54 pg/mL/year), as well as faster hippocampal atrophy over time. Among treated participants, CPAP adherence was associated with improved cognition (MoCA: +0.59; ADAS-Cog: -1.48) and reductions in IL-6 (-0.95 pg/mL), GFAP (-14.67 pg/mL), and NfL (-2.33 pg/mL).

CONCLUSIONS

In patients with AD, OSA was associated with a more adverse A/T/N biomarker profile, broader neuroimaging abnormalities, including altered DTI-ALPS index and choroid plexus volume as indirect imaging markers of potential glymphatic-related dysfunction, and faster neurodegenerative progression. CPAP adherence was associated with more favorable short-term trajectories, suggesting that OSA may be a clinically relevant and potentially modifiable contributor to disease burden in AD.