Moderate-to-Severe OSA Linked to Doubled Risk of Brain Microbleeds Over 8 Years: New Research

Middle-aged and older adults with moderate to severe obstructive sleep apnea (OSA) face more than double the risk of developing cerebral microbleeds over an 8-year period compared to those without the sleep disorder, according to new research published in JAMA Network Open.¹

The prospective cohort study of 1,441 Korean adults found that participants with an apnea-hypopnea index of 15 or greater had a relative risk of 2.14 (95% CI, 1.08-4.23) for incident cerebral microbleeds at 8 years, even after adjustment for traditional vascular risk factors including hypertension, diabetes, and cholesterol levels. The association remained significant regardless of APOE-ε4 carrier status.¹

Notably, the increased risk was not apparent at 4-year follow-up, and mild OSA showed no significant association with microbleed development at any time point, according to the authors, led by Ali Tanweer Siddiquee, MBBS, PhD, from the Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital in Ansan, Republic of Korea.¹

Microbleeds Signal Early Pathology

Cerebral microbleeds—the hypointense ovoid lesions visible on gradient-recalled echo imaging due to blood degradation products in brain tissue—represent early markers of cerebrovascular pathology and are associated with increased risk of symptomatic stroke and dementia.² Their prevalence ranges from 3% in middle-aged individuals to 23% in older populations, climbing to 50-70% in patients with established cerebrovascular disease.³

Previous research on the OSA-microbleed connection has yielded mixed results, with several meta-analyses finding no significant associations. However, most prior studies were cross-sectional with smaller sample sizes, and none had examined the relationship longitudinally.

"To our knowledge, no study to date has investigated the association between OSA and risk of incident CMBs longitudinally," Siddique and colleagues wrote. This is the first prospective cohort study to report moderate to severe OSA as an independent risk factor associated with incident CMBs in a large general population of adults, they stated.¹

Tapping the Korean Genome and Epidemiology Study

Researchers drew participants from the Korean Genome and Epidemiology Study (KoGES), an ongoing longitudinal investigation. Between 2011 and 2014, participants underwent baseline in-home polysomnography and brain MRI, with follow-up assessments at 4-year intervals through 2022.

OSA severity was categorized by apnea-hypopnea index (AHI) as: no OSA (0-4.9 events/hour), mild OSA (5.0-14.9 events/hour), and moderate to severe OSA (15.0 or more events/hour). The study excluded participants with baseline microbleeds, history of cerebrovascular or cardiovascular disease, or missing covariates.

At baseline, the mean participant age was 57.75 years, and 52.67% were women. Thirty percent had mild OSA and 13.4% had moderate to severe OSA. In the subgroup with moderate to severe OSA, the authors noted that BMI was higher, hypertension and diabetes were more prevalent, and participants were more likely to be male, current smokers, and current drinkers.

Key Findings

The cumulative incidence of cerebral microbleeds was:

• At 4 years: 1.85% (no OSA), 1.61% (mild), 4.66% (moderate to severe)
• At 8 years: 3.33% (no OSA), 3.21% (mild), 7.25% (moderate to severe)

Siddiquee and team observed that most incident microbleeds were single lesions with lobar location. In multivariable models that adjusted for demographics, cardiovascular risk factors, white matter changes, and longitudinal changes in AHI and BMI, only the 8-year risk for moderate to severe OSA remained significantly elevated.

Sensitivity analyses excluding the 21 participants who used CPAP during follow-up yielded essentially identical results. Additional adjustment for APOE-ε4 genotype in a subsample of 1,233 participants showed an even higher relative risk of 2.91 (95% CI, 1.29-6.58), though the authors attributed the increased magnitude to differential loss of participants between groups.

Potential Mechanisms

While the pathophysiology linking OSA to microbleeds is not completely clear, the authors proposed several mechanisms. Although hypertension commonly accompanies OSA, the association persisted after adjustment for blood pressure, suggesting additional pathways may be involved.¹

"Oxidative stress leads to production of free radicals, which may damage cell structure, including brain vasculature, potentially contributing to CMBs," the authors noted. "Chronic hypoxia can also trigger inflammatory responses, leading to endothelial dysfunction and increased vascular permeability, making vessels more susceptible to bleeding."¹

OSA's known association with cardiac arrhythmias, particularly atrial fibrillation, may also play a role, as AF itself has been linked to higher microbleed prevalence.⁴

Limitations. Among the study's limitations the authors acknowledged that the low prevalence of APOE-ε4 carriers in the Korean cohort limited stratified genetic analyses. Also, the low number of incident microbleeds prevented adequate assessment of their spatial patterns or burden and the type of imaging may also have led to understimating the number of microbleeds. Finally, Siddiquee et al pointed out that the healthy cohort effect over the 20 years of follow-up may limit generalizability of their findings

"Given that OSA is a modifiable risk factor, this finding suggests that moderate to severe OSA should be a potential target for early diagnosis and treatment to prevent incident CMBs and potentially prevent future strokes and dementia in aging populations," the authors concluded.

The study adds to growing evidence linking sleep-disordered breathing to brain health outcomes and suggests that OSA screening and treatment may represent an underutilized strategy for cerebrovascular disease prevention in middle-aged and older adults, they added.