Obstructive sleep apnea, cognition and Alzheimer's disease: A systematic review integrating three decades of multidisciplinary research

Abstract

Increasing evidence links cognitive-decline and Alzheimer's disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). With increasing age, there are substantial differences in OSA's prevalence, associated comorbidities and phenotypic presentation. An important question for sleep and AD researchers is whether OSA's heterogeneity results in varying cognitive-outcomes in older-adults compared to middle-aged adults. In this review, we systematically integrated research examining OSA and cognition, mild cognitive-impairment (MCI) and AD/AD biomarkers; including the effects of continuous positive airway pressure (CPAP) treatment, particularly focusing on characterizing the heterogeneity of OSA and its cognitive-outcomes. Broadly, in middle-aged adults, OSA is often associated with mild impairment in attention, memory and executive function. In older-adults, OSA is not associated with any particular pattern of cognitive-impairment at cross-section; however, OSA is associated with the development of MCI or AD with symptomatic patients who have a higher likelihood of associated disturbed sleep/cognitive-impairment driving these findings. CPAP treatment may be effective in improving cognition in OSA patients with AD. Recent trends demonstrate links between OSA and AD-biomarkers of neurodegeneration across all age-groups. These distinct patterns provide the foundation for envisioning better characterization of OSA and the need for more sensitive/novel sleep-dependent cognitive assessments to assess OSA-related cognitive-impairment.

Keywords: Alzheimer's disease; Amyloid; Biomarkers; Cognition; Middle aged; Mild cognitive impairment; Obstructive sleep apnea; Older adults; Phosphorylated tau.

Fig. 1.

Study retrieval and selection for obstructive sleep apnea, cognition and Alzheimer’s disease systematic review.

Fig. 2.

Possible intermediate mechanisms in the relationship between OSA and Cognitive Dysfunction in the middle-aged. Chronic exposure to intermittent hypoxia, excessive daytime sleepiness (EDS), disruption of restorative sleep from sleep fragmentation and increase in AD neuropathology may lead to increased cognitive dysfunction. EDS and disruption of restorative sleep are more pronounced in the middle-aged relative to the elderly. Cognitive dysfunction is mainly mediated via cardiovascular and metabolic injuries. Cardiovascular effects of OSA including hypertension, coronary heart disease, congestive heart failure and stroke can also lead to increase in AD neuropathology while metabolic injury effects including diabetes, increased pro-inflammatory cytokines and impaired sympathetic tone from disruption of restorative sleep can further impair sleep supported cognitive processes. OSA, obstructive sleep apnea; and AD, Alzheimer’s disease.

Fig. 3.

Possible intermediate mechanisms in the relationship between OSA and Cognitive dysfunction in older adults. Chronic exposure to intermittent hypoxia may lead to increased inflammation and oxidative stress, diabetes, hypertension and CVD, all potentially contributing to AD pathology development. Sleep fragmentation, both by itself and by leading to decreased REM and SWS stages, can additionally promote AD pathogenesis. Intrathoracic pressure swings associated with OSA may disrupt CSF-ISF exchange integrity and lead to AD neuropathology accumulation. Furthermore, all the processes including hypoxia, fragmented sleep and intrathoracic pressure swings can cumulatively lead to decreased neural plasticity and neuronal loss and atrophy, thereby contributing to cognitive dysfunction. OSA, obstructive sleep apnea; CVD, cardiovascular disease; REM, rapid eye movement; SWS, slow wave sleep; CSF-ISF, cerebrospinal fluid-interstitial fluid; AD, Alzheimer’s disease.