OSA is increasingly recognized not only as a cardiovascular risk factor but also as a potential contributor to neurodegeneration. As interest grows in early interventions for Alzheimer’s disease (AD), sleep disorders like OSA are thought to be potentially modifiable factors in the AD continuum. AD pathology, including beta-amyloid (Aβ) biomarker framework introduced in 2018, formalizes this preclinical stage by categorizing pathology into amyloid, tau, and neurodegeneration, which are measurable via PET imaging, or in fluids such as spinal fluid or plasma. This framework enables uniform staging of disease, allows for early detection via biomarkers, and can help to recruit appropriate participants for AD-related trials.
OSA’s impact on AD biomarkers
Increasing evidence now suggests that OSA may influence all three components of this framework. Both cross-sectional and longitudinal studies have demonstrated positive associations between untreated moderate to severe OSA and elevations in Aβ and tau burden on PET imaging in adults who are cognitively older, independent of age and apolipoprotein E-ε4 status.2 Additionally, experimental models using acute withdrawal of positive airway pressure (PAP) have demonstrated that even short-term reintroduction of OSA physiology can lead to significant increases in AD biomarkers. For example, one study found that acute discontinuation of PAP therapy in adherent patients with OSA led to measurable overnight increases in plasma Aβ and neurofilament light, a biomarker associated with neurodegeneration.3 Taken together, these findings suggest that OSA is a plausible accelerator of preclinical AD, and they demonstrate a highly dynamic relationship between sleep-disordered breathing and AD-related neuropathology. They underscore the potential for therapeutic interventions to modify disease risk and long-term cognitive outcomes.
Mechanisms linking OSA to AD pathophysiology
Multiple mechanisms may explain how OSA contributes to AD pathology. First, intermittent hypoxia and sleep fragmentation, hallmarks of OSA, may lead to increased cortical neuronal firing, driving the production of Aβ and tau and accelerating plaque and tangle formation.4 This excessive neuronal activity has been shown in both animal models and human studies to correlate with increased amyloid and tau production, particularly during periods of wakefulness. Additionally, glymphatic clearance of neurotoxic waste, most active during slow-wave sleep, is often disrupted in OSA, potentially reducing amyloid clearance.5 Contraction of brain cell volume during sleep is thought to expand the interstitial space, opening avenues to remove metabolic waste, including Aβ, through cerebrospinal fluid flow.
Furthermore, intermittent hypoxia can induce oxidative stress and neuronal injury in vulnerable regions like the hippocampus, triggering mitochondrial dysfunction, microglial activation, and apoptosis, all of which contribute to neurodegenerative cascades.4 These mechanisms can compound over time, potentially priming the brain for early neurodegenerative changes that precede clinical symptoms. Lastly, OSA-related systemic and central inflammation, through chronic immune dysregulation and blood-brain barrier compromise, are recognized as contributors to tau phosphorylation and neuronal degeneration.4 Importantly, this relationship is bidirectional. AD pathology disrupts sleep, especially slow-wave sleep, by damaging brain regions that regulate arousal and circadian rhythms, including potentially reducing the respiratory arousal threshold, making arousals from partial upper airway collapse more likely. Loss of slow-wave sleep is typically accompanied by increases in light non-REM stage 1 sleep, a greater arousal index, shorter sleep stage bout lengths, and greater wake after sleep onset, which can all occur independently of sleep apnea. Such sleep disruptions are thought to reduce glymphatic clearance, potentially accelerating Aβ and tau accumulation.6
In summary, this chronic feedback loop between disrupted sleep and AD pathology may help explain the early presence of sleep disturbances in preclinical AD seen in some individuals.
Treatment: PAP therapy and cognitive functioning
Treatment of OSA with PAP therapy can reduce sleepiness, improve quality of life, and reduce hypertension. While treatment of OSA has not yet been proven to slow AD pathology, emerging evidence suggests it can meaningfully alter cognitive outcomes. Observational studies have shown that individuals with OSA who use PAP therapy exhibit slower cognitive decline compared with individuals who remain untreated. In the Alzheimer’s Disease Neuroimaging Initiative cohort, self-reported CPAP use in individuals with self-identified OSA was associated with a 10-year delay in the onset of mild cognitive impairment vs untreated OSA.7 Another study analyzing Medicare claims data from more than 53,000 older adults with OSA demonstrated that PAP treatment was associated with 22% lower odds of developing AD.8
More recently, a randomized controlled trial by Xu and colleagues investigated the neurofunctional effects of PAP therapy on brain connectivity in patients with OSA defined by AHI3A > 15/hour.9 The study enrolled treatment-naïve participants who were randomly assigned to either therapeutic PAP or best supportive care as the control with primary outcomes assessed at six months. Resting-state functional MRI was performed at baseline and after the intervention to assess brain network changes, with a particular focus on the default mode network (DMN), a hub for memory consolidation and one of the earliest brain networks disrupted in AD. After six months, individuals in the therapeutic PAP group showed significant increases in functional connectivity within the posterior cingulate cortex and precuneus regions of the DMN compared with the control group. These changes were independent of improvements in daytime sleepiness, suggesting a direct impact of PAP on neural networks rather than simply behavioral alertness. This study provides further evidence that even short-term treatment with PAP can reverse functional network disruptions, reinforcing the idea that sleep interventions may offer a window of neuroplastic opportunity in individuals at risk for cognitive decline.
Lastly, in a separate clinical trial, Djonlagic and colleagues investigated the impact of three months of PAP therapy on sleep-dependent memory and sleep architecture in individuals with OSA.10 Patients with OSA performed significantly poorer than patients without OSA on an overnight word-pair declarative memory task. Subsequently, patients with OSA randomized to PAP treatment for three months demonstrated significantly improved overnight memory compared with patients randomized to a three-month wait-list, with memory performance approximating that in subjects without OSA. Increases in N3 sleep from the baseline night predicted the increase in overnight word-pair memory improvement between the baseline and follow-up session. These findings suggest that PAP therapy not only improves cognitive deficits associated with OSA but also restores aspects of sleep architecture critical for cognitive processes. The study highlights the potential of PAP treatment to mitigate cognitive impairments and normalize sleep neurophysiology in individuals with OSA.
Take-home messages
Given the prevalence of OSA and the long preclinical phase of AD, early identification and treatment of sleep apnea represent important opportunities for intervention. Sleep clinicians and pulmonologists are uniquely positioned to screen for OSA in at-risk populations and emphasize the potential downstream cognitive benefits of adherence to therapy. Even if treatment does not halt the trajectory of AD pathology, its potential to improve quality of life, cognition, and functional independence should not be underestimated.
Looking ahead, ongoing research continues to explore how best to translate these findings into broader clinical practice. One such effort is the ESSENTIAL (The Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts) clinical trial (NCT05988385), in which older individuals aged 55 years to 85 years with a new diagnosis of OSA are randomized to treatment with their choice of PAP, oral appliance therapy, and/or positional therapy vs a three-month wait-list. This study is testing the impact of AHI reduction, irrespective of treatment approach, on overnight memory and plasma AD biomarkers, and it will hopefully shed further light on this topic. As such investigations advance, OSA treatment may prove not only effective for improving sleep but also instrumental as an early, modifiable intervention to slow or mitigate cognitive decline.
This article was originally published in the Summer 2025 issue of CHEST Physician.
References
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