Biomarkers

Background: Obstructive sleep apnea (OSA) is associated with hypoxia-induced neuronal impairment and dysfunction-key risk factors for the pathogeneses of age-related neurodegenerative diseases such as Alzheimer's disease (AD). This study examined longitudinal associations between OSA severity and CSF biomarkers associated with AD, synaptic dysfunction, and neuroinflammation in a sample of late-middle-aged adults with increased risk for AD.

Method: N=25 cognitively unimpaired adults (64% female, mean age 65.8 ± 7.1 years, 42.3% APOE-ε4 carriers) from the Wisconsin Alzheimer's Disease Research Center (ADRC) participated in overnight polysomnography, where the number of apneas, hypopneas, and respiratory effort related arousals (RERAs) per hour of sleep were recorded. OSA severity was estimated using the base 10 logarithm of the Respiratory Disturbance Index, or log₁₀(RDI+1). Following sleep assessment, CSF samples were acquired via lumbar puncture over two subsequent study visits (mean 5.8 years between visits) and analyzed using the NeuroToolKit (NTK), a panel of robust prototype assays (Roche Diagnostics International Ltd), with measures including core AD biomakers-amyloid beta (Aβ)₄₂, Aβ₄₂:Aβ₄₀, pTau₁₈₁, pTau₁₈₁:Aβ₄₂, and tTau-as well as neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), neuronal pentraxin II (NPTX2), and synaptosome associated protein 25 (SNAP25). Linear mixed effects models (with random intercept and random slope) were assembled to test longitudinal associations, adjusting for age, sex, and APOE-ε4 carriage.

Result: AD biomarker models indicated that RDI was associated with increased CSF levels of tTau (β=0.084, SE=0.013, p=0.014) and pTau₁₈₁ (β=0.022, SE=0.003, p=0.023), but neither outcome remained robust after Bonferroni correction for multiple comparisons (adjusted α=0.0039). In contrast, models of synaptic dysfunction and neuroinflammation surpassed Bonferroni correction, showing a significant association between RDI and levels of α-synuclein (β=0.09, SE=0.013, p=0.002) and neurogranin (β=0.13, SE=0.03, p=0.002).

Conclusion: This work provides new evidence for the deleterious influence of OSA on biomarkers of synaptic dysfunction, neuroinflammation, and AD in a sample of late-middle age to older adults enriched with risk for AD.