OSA: A risk factor for earlier cognitive decline

Increasing evidence indicates that obstructive sleep apnoea (OSA) is associated with cognitive decline. Therapy with continuous positive airway pressure (CPAP) has demonstrated not only to improve various cognitive tests, but also to reduce biomarkers associated with Alzheimer´s disease (AD).

Neuropathologic hallmarks of AD are abundant amyloid plaques containing β amyloid, neurofibrillary tangles, and dystrophic neurites containing hyperphosphorylated tau. How sleep-disordered breathing might impact cognition was assessed in the ADNI cohort, an active cohort including 2,470 subjects with an average follow-up of 2–3 years. A subset of 767 subjects was available for sleep analysis. They completed sleep questionnaires, were asked whether they have sleep apnoea and if yes, whether they use CPAP. In this subset of patients, age of mild cognitive impairment (MCI) diagnosis could be determined. “One of the advantages of this cohort is that these subjects were followed closely with progressive neuropsychological tests, so exact stages of transition from low cognition to MCI, an early stage of AD, could be precisely determined,” said Prof. Andrew W. Varga (Mount Sinai Integrative Sleep Center, NY, USA) [1]. A previous study examined whether the presence of OSA is associated with an earlier age at MCI or AD onset in this cohort [2]. Results indicated that the age of onset of MCI was reduced in older subjects with sleep-disordered breathing. “There was a marked difference of 11 years,” Prof. Varga explained. “However, those treated with CPAP had a much later onset,” he said. Their risk of MCI was comparable to those who did not have sleep-disordered breathing.

CPAP use improves memory tests

A positive influence of CPAP on memory deficits could also be demonstrated in a second case-control study including 36 patients with newly diagnosed OSA and 36 matched healthy controls [3]. Primary outcome was improvement in a declarative memory test (verbal paired-associate task [VPA]). The overnight testing included a training session of the task in the evening followed by a polysomnogram and a VPA recall test in the morning. The groups had similar performances in the evening. The following morning, patients with OSA correctly completed on average 74.1% of the word pairs, a 7.1% increase from the evening before, compared with 82.4% in the healthy controls, a 13.9% increase – almost twice that of the OSA group [3]. Subjects with OSA were then randomly assigned to a CPAP group and a no-CPAP group. After 3 months, both groups returned for overnight testing, including evening training and morning recall. The polysomnogram revealed that the CPAP group had more than twice as much stage 3 (N3) sleep compared with the non-CPAP group. In addition, the CPAP group achieved test results similar to healthy controls and significantly better than the no-CPAP group. Between the CPAP and no-CPAP group was a mean difference of 6.21% (95% CI 1.08–11.34). “These results demonstrated that the deficit in remembering words is a result of OSA and this can be reversed by CPAP,” Prof. Varga commented. Increases in N3 sleep from the baseline night predicted the increase in overnight VPA memory improvement between the 2 test sessions (r=0.34; P=0.04). A similar study performed by Prof. Varga and co-workers demonstrated that OSA alters morning performance in spatial navigation memory processing (tested with a 3D maze environment) [4]. In the evening, no difference was observed between participants with and without OSA. However, OSA altered the morning performance independent of deleterious effects on morning vigilance or evening navigation.

OSA severity is associated with increases in cortical amyloid deposits

Another trial tested the hypothesis that there is an association between severity of OSA and longitudinal increases in amyloid burden in cognitively normal elderly [5]. Data were derived from a 2-year prospective longitudinal study. All subjects were healthy and cognitively normal volunteers aged 55–90. Cerebrospinal fluid (CSF) amyloid β was measured using ELISA and positron emission tomography (PET). A subset of 34 subjects completed a second amyloid PET scan at 2.5 years.

In this study, the severity of OSA indices was associated with a longitudinal decrease of cerebrospinal fluid amyloid β₄₂ – even after adjustment for confounding risk factors. “Longitudinal decrease in soluble amyloid β₄₂ in CSF reflected an increase in insoluble β-amyloid plaques found in the brain,” Prof. Varga said. This could be verified in the subset of patients undergoing PET imaging: higher OSA severity at baseline was associated with a longitudinal increase in cortical amyloid deposits.

Finally, Prof. Varga discussed whether chronic OSA treatment can impact AD fluid biomarkers over time. This question was assessed in a study including 35 adults with OSA that were prescribed CPAP [6]. CSF was collected before the start of treatment and 1–4 months after treatment. The analysis was limited to CPAP-adhering subjects (18/35 patients). Overall, no significant differences were observed in the biomarkers tau and total protein pre- and post-treatment. Nonetheless, significant negative correlations were observed in the change of apnoea-hypopnoea index and amyloid β biomarkers. “This suggests that there may be a threshold in the apnoea-hypopnoea index that is needed to detect significant changes in some of these fluid biomarkers of AD chronically over time,” Prof. Varga concluded.

1. Varga A. Is OSA a risk factor for cognitive decline and Alzheimer’s Disease. Session A025: Sleep disorders: The new risk factor for age-related neurodegenerative diseases. ATS 2021 International Conference, 14-19 May.
2. Osorio RS, et al. Neurology 2015;84(19):1964-71.
3. Djonlagic IE, et al. Am J Resp Crit Care 2021;203(9);1188-90.
4. Mullins AE, et al. J Clin Sleep Med 2021;17:939-48.
5. Sharma RA, et al. Am J Resp Crit Care 2018;197(7): 933-43.
6. Ju YE S, et al. Ann Neurol 2019:85:291-5.

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Posted on 5 July, 202125 March, 2024