The Overlooked Role of Obstructive Sleep Apnea in Alzheimer Pathogenesis

Ominigho Michael Bubu, MD, PhD

In recent years, sleep medicine and neurodegeneration have become increasingly linked, as research shows that poor sleep may accelerate the buildup of neurotoxic protens like beta-amyloid and tau. Sleep disturbances are also emerging as early signs or risk factors in conditions such as Alzheimer and Parkinson diseases, positioning sleep as both a diagnostic and therapeutic target.

Reflecting on this growing connection, the SLEEP Annual Meeting, held June 8-11 in Seattle Washington, expanded its programming to welcome more neurologists and neuroscientists, providing a platform to explore how sleep-related mechanisms interest with neurodegenerative pathology. Among the attendees was Ominigho Michael Bubu, MD, PhD, an associate professor of psychiatry, neurology, and population health at NYU Langone, who presented on the impact of obstructive sleep apnea (OSA) on neurodegenerative and AD pathogenesis.

Following the meeting, NeurologyLive^® caught up with Bubu to discuss the findings from his presentation exploring the physiologic, race-, and sex-specific links between OSA and AD. In the interview, he covered how OSA mechanisms such as hypoxia and sleep fragmentation may accelerate AD risk and progression, with marked differences observed across racial and gender lines. Bubu, who also serves as the director for Aging Research in Sleep Equity and Dementia Prevention (ARISE-DP) also outlines potential pathways—such as impaired glymphatic clearance and OSA-Aβ synergism—by which OSA may contribute to amyloid and tau accumulation.

Can you provide a brief overview of your presentation and why this was a topic of interest for you?

Ominigho Michael Bubu, MD, PhD: Obstructive sleep apnea (OSA) is associated with increased Alzheimer Disease (AD) risk, with studies showing altered levels of both established and novel biofluid AD biomarkers in cross-sectional and longitudinal analyses. There is debate whether OSA can precede AD onset. The presentation examined whether OSA is associated with incident clinical AD diagnosis over a follow-up period extending from 8 to 15 years. The presentation also examined mechanisms specific to OSA including hypoxia, duration and fragmentation measures and how these may increase AD risk. The presentation also examined whether these mechanisms were racial/ethnic and /or sex specific. We also tried to characterize and identify patients with OSA who may have the greatest risk of progression through the stages of AD.

How does OSA impact different races and genders?

Black/African American and Hispanic individuals are twice as likely to be sleep deprived, have the highest burden of symptomatic obstructive sleep apnea (OSA), particularly with excessive daytime sleepiness, relative to non-Hispanic white individuals. Sex-specific evidence on OSA risk suggest that OSA is more common in men than women in the general population with a male-to-female ratio of approximately 1.5:1. In addition, studies show women compared to men independent of age, weight and influence of medications, such as anti-depressants having lower AHI, less severe OSA in non-rapid eye movement (NREM) sleep, more partial obstruction and shorter events, more respiratory effort related arousal (RERA) events and upper airway resistance syndrome (UARS), and higher prevalence of rapid eye movement (REM) related sleep apnea events

Are there race and sex-specific biologic mechanisms of the relationship between obstructive sleep apnea (OSA) and incident AD?

The summary of our findings are shown below:

• Relative to whites, Black/African American and Hispanic older adults were significantly more likely to have increased risk for incident AD in measures of hypoxia, and sleep duration. (P <.01 for all)
• Relative to males, females were significantly more likely to have increased risk for incident AD in measures of sleep fragmentation. (P <.01 for all)
• Relative to females, males were significantly more likely to have increased risk for incident AD in measures of hypoxia. (P <.01 for all)
• Sleep fragmentation and duration measures’ effects on AD risk were similar for races and sexes respectively.

Based on these data, we think that in older patients with OSA, mechanisms possibly related to hypoxia, sleep fragmentation and sleep duration measures might underlie AD race and sex-related disparities.

How might intermittent hypoxia and sleep fragmentation in OSA contribute to amyloid or tau accumulation in the brain?

Our findings support the hypothesis of an overarching model of late-onset AD with brain amyloid deposition and tau aggregates proceeding at different rates. This model of AD implies a contributory role of OSA, first with the direct potential for neuronal injury independent of Aβ irrespective of MCI/AD progression risk. This direct neuronal injury can occur with intermittent hypoxemia that can compromise oxygenation of the brain neuronal cells. Other inflammatory pathways can also be triggered. Second, an indirect contributory role of OSA which may accelerate Aβ & tau accumulation in the presence of Aβ plaques via a feedback loop. This role of OSA significantly increases MCI/AD progression risk. Third, a contributory role of an OSA-Aβ synergism that significantly increases MCI/AD progression risk and possibly accelerates AD biomarker changes leading to shorter time-to-MCI/AD in OSA Cognitively Normal and Mild Cognitive Impairment participants respectively. This OSA-Aβ synergism related to cognitive decline can be independent of tau as well as synergistic with tau deposition. Fourth, sleep fragmentation can impact time spent in Slow Wave Sleep (SWS). Together with intrathoracic pressure swings that can impact CSF-ISF exchange, reduced SWS can impact brain clearance mechanisms, thus possibly leading to impaired glymphatic clearance of amyloid and tau.

The connection between OSA and neurodegeneration has become more established, but how do we convey that to the public? Should there be more awareness efforts discussing the interplay between the two?

We should let the public know that sleep problems generally and particularly OSA are a risk factor for cognitive decline and dementia or Alzheimer's Disease. This is important, as data suggests that around 15 percent of Alzheimer’s disease cases can be attributed to specific sleep problems. This can be translated to mean that if we can eliminate sleep problems before major cognitive decline, we may be able to significantly reduce the Alzheimer’s disease risk burden—particularly among Black and Hispanic patients.Providers also need to prioritize sleep in patient education and promote adherence to effective treatments for sleep problems; by doing this, physicians may be able to help their patients effectively slow the onset and progression of cognitive decline

Are there specific biomarkers–imaging, CSF, or otherwise–that show differential changes in OSA patients with higher risk for neurodegenerative disease?

Yes, OSA severity is associated with longitudinal increase in amyloid burden in cognitively normal older adults. Both cognitively normal and MCI patients with OSA have an increased annual rate of worsening change in brain amyloid burden and tau protein aggregation. Cognitively normal subjects with OSA show greater amyloid burden, gray matter volume, perfusion and metabolism overlapping mainly over the posterior cingulate cortex and precuneus areas of the brain. This increase in gray matter volume may be a sign of inflammation in the initial stages. With disease progression, the gray matter losses then occur as a result of neurodegeneration.

Should screening for OSA be more common in Alzheimer trials? What benefit would this bring, if feasible?

I would say yes. Our data suggests that OSA is a modifier of AD risk. We see a contributory role of an OSA-Aβ synergism that significantly increases MCI/AD progression risk and possibly accelerates AD biomarker changes leading to shorter time-to-MCI/AD in OSA cognitively normal and mild cognitively impaired participants respectively. This OSA-Aβ synergism related to cognitive decline can be independent of tau as well as synergistic with tau deposition. Importantly, the co-occurrence of OSA and hypertension interact synergistically to promote β-Amyloid burden, and global cognitive decline. Screening for OSA may help identify individuals who may benefit from interventions targeted at OSA specifically that we know can be effective with adequate adherence, as well as the AD specific treatments, to optimize treatment outcomes.

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