Bryce Mander is an Assistant Professor in the Department of Psychiatry and Human Behavior at the University of California, Irvine (CA, USA). His research focuses on the relationships between sleep and cognition across the lifespan, with a special focus on the role of sleep disturbance in age-related cognitive decline and Alzheimer’s disease (AD) pathophysiology. Of particular interest to him is the interaction between AD biomarkers and sleep, and their impact on sleep-dependent memory. His long-term vision is to determine if sleep interventions can slow the progression of AD pathophysiology and reduce cognitive decline associated with AD.
In this interview, Bryce speaks more about his work on this, which is beginning to demonstrate that associations between various aspects of sleep and AD are present in cognitively normal adults before mild cognitive impairment or AD diagnoses, and potentially even before amyloid plaque deposition.
Could you tell us more about the talk you were supposed to be giving at the Alzheimer’s Research UK Conference (17–18 March 2020, Newport, UK) on novel models for dementia?
The talk focused on relationships between fluid biomarkers of AD assessed in cerebrospinal fluid (CSF) and the local expression of sleep oscillations known to be associated with the long-term consolidation of episodic memories in cognitively healthy middle-aged and older adults (ages 48–86) at increased risk for AD due to family history or APOE4 positivity. This cohort was largely amyloid plaque and neurofibrillary tangle negative based on established CSF cut-offs. In other words, this abstract examined relationships between the local expression of brain waves during sleep and AD biomarkers even prior to amyloid plaque deposition. We focused on this because we were interested in examining if sleep deficits are observed even in the earliest stages of AD pathogenesis.
The biomarkers we examined included classic markers of AD pathology such as the ratio of amyloid-β 42/40, ptau, and ttau, and also markers of glial activation (YKL-40), axonal degeneration (neurofilament light protein; NFL) and synaptic degeneration (neurogranin). Each of these track processes related to inflammation, AD pathology and neurodegeneration. The brain waves during sleep that we examined are called slow waves and sleep spindles, and they are expressed in specific brain networks and support the consolidation of hippocampus-dependent memories.
Our findings were that the intensity of sleep spindle expression over frontal cortex was reduced in individuals with higher levels of ttau and ptau, or had higher levels of YKL-40, NFL, or neurogranin. Sleep spindles were unaffected by the amyloid-β 42/40 ratio. Lastly, this work determined that age predicted higher levels of YKL-40 and the influence of this inflammation marker on sleep spindles was mediated by its effects on ttau, ptau and neurogranin. In other words, age-related inflammation may be associated with higher tau protein levels and synaptic degeneration, which are more directly linked with sleep spindle disruption over the prefrontal cortex.
You’ve conducted research that supports the emerging hypothesis that sleep disruption contributes to the initial pathophysiology of Alzheimer’s disease – can you tell us more about this?
Our work, and others, are beginning to show that the associations between various aspects of sleep and AD are present in cognitively normal older adults before mild cognitive impairment or AD diagnoses and even potentially before amyloid plaque deposition. These relationships appear to be bidirectional in nature, with sleep disorders increasing AD risk and sleep deprivation increasing AD-relevant proteins in studies of humans and rodents.
Moreover, these studies show that the sleep deficits linked to AD biomarkers are associated with memory deficits even in healthy older adults. This study builds on this work, showing how different AD biomarkers interact to influence sleep. In short, our data support the hypothesis that age-related inflammation triggers increased production of AD pathologies, which in turn disrupts neuronal integrity supporting the expression of sleep oscillations critical for sleep-dependent memory consolidation. Ultimately, this indicates that sleep deficits occur early during the initial stages of AD pathogenesis and that they may have functional consequences related to the earliest expression of AD-related cognitive impairment.
What are the challenges in conducting research into sleep disruption and Alzheimer’s pathophysiology?
A big challenge in this area of work is determining the causal nature of these relationships; whether they are actively contributing to AD progression or are an early marker of disease processes. Another remaining challenge is determining the mechanistic specificity of these relationships between AD and sleep, and their utility in differential diagnosis. Very little is known regarding sleep deficits seen in other forms of dementia, and their role in dementia pathophysiology.
How could these challenges be addressed?
Large-scale longitudinal sleep intervention studies that target various aspects of sleep disturbance that are related to AD risk and progression will be necessary to tease apart these possibilities. Ultimately, the answer may differ depending on which sleep disturbance feature is examined. Pathophysiology of sleep apnea and insomnia may be more likely to contribute to disease progression, while other forms of sleep deficits, like loss of REM sleep desynchrony, may reflect underlying disease processes like the degeneration of the cholinergic system. Addressing differential diagnosis, more work needs to be conducted in a variety of neurodegenerative diseases and in a variety of forms of AD, including that observed in Down syndrome and early-onset AD.
Lastly, what developments are you most excited to see in the field? Where do you hope we could be in 5–10 years’ time?
Advances in the use of a variety of PET, plasma and CSF methods will allow for a targeting of combinations of unique AD risk factors at an unprecedented level of detail and scope. This will allow for a more nuanced examination of the mechanistic links between sleep deficits and dementia pathophysiology across forms of neurodegenerative disease. Moreover, advances in brain stimulation methods and their use to locally enhance the expression of brain waves during sleep may offer exciting new possibilities in enhancing microfeatures of sleep that are deficient in those at risk for AD or in those progressing through AD stages.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
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