The Emerging Role of Sleep in the Development of Alzheimer Disease

Possible Mechanisms

Possible mechanisms have been suggested to explain how poor sleep may lead to AD. Over the past 10 years, sleep deprivation was found to increase Aβ concentrations in both a mouse model (Kang JE, et al. Science. 2009; 326:1005) and humans, most likely through increased production and/or release of Aβ (Lucey BP, et al. Ann Neurol. 2018; 83[1]:197). Sleep also appears to increase clearance of proteins and other molecules via bulk fluid flow (“glymphatic” clearance). Glymphatic clearance may enable the removal of interstitial toxic proteins, such as Aβ, through a dynamic interaction between the cerebrospinal fluid and the interstitial fluid, where astrocytes facilitate extracellular fluid transit though the brain during sleep (Xie L, et al. Science. 2013;342:373). Since Aβ deposition in the brain is concentration-dependent, higher Aβ levels from sleep disturbance could lead to greater deposition in the brain.
 

Circadian Rhythm and Alzheimer Disease

Another mechanism linking sleep to the pathogenesis of AD includes disruption of the circadian rhythm, which is commonly seen in patients with AD. Studies have linked populations who suffer from circadian rhythm disorders to higher rates of dementia (Tranah GJ, et al. Ann Neurol. 2011;70[5]:722). Circadian disruption may predispose the brain to neurodegenerative conditions by altering immune function, disrupting endocrine function, increasing inflammation and oxidative stress, or affecting neurogenesis (in specific areas such as the hippocampus). Thus, inadequate sleep could prime the brain for neurodegeneration by multiple pathways.
 

Obstructive Sleep Apnea and Alzheimer’s Disease

Sleep disruption and chronic intermittent hypoxia secondary to untreated OSA has also been associated with AD. Numerous studies have shown that sleep-disordered breathing is associated with AD risk and that AD patients have higher rates of OSA. For instance, a study in older women found that moderate and severe sleep-disordered breathing was associated with an increased risk of future cognitive impairment and dementia (Yaffe K, et al. JAMA. 2011[Aug]:10;306[6]:613). In addition to sleep disruption from sleep apnea affecting Aβ as detailed above, hypoxia from sleep apnea may also alter risk of future AD.
 

Future Directions

Studies support a clear bidirectional relationship between AD and sleep. As researchers continue to investigate sleep as a marker for AD, others are exploring the implications of using sleep interventions to prevent and/or delay the onset of AD. Patients with poor and disrupted sleep may be the ideal candidates for sleep interventions to lower the risk of AD, such as treating OSA with CPAP therapy or insomnia with hypnotic medication or cognitive behavioral therapy. These therapies are already well-studied and approved for human use, allowing for rapid translation to future intervention trials.

Dr. Malhotra is Associate Professor, Sleep Medicine Section; and Dr. Lucey is Assistant Professor, Director-Sleep Medicine Section; Department of Neurology, Washington University School of Medicine, St Louis, Missouri.