Disturbed Sleep in Preclinical Cognitive Impairment: Cause and Effect?

Cognitive decline in old age, particularly impairments associated with neurodegenerative dementias such as Alzheimer disease (AD), represents one of the largest public health and economic challenges of the 21st century. The current annual societal cost of dementia outstrips the cost of heart disease and cancer.¹ With 10% of adults over 65 now suffering from dementia,^1,3 and this number projected to double over the next forty years,^3,4 understanding the factors responsible for cognitive decline is of critical importance. Dementia neuropathology, such as AD-linked β-amyloid aggregation and cerebral infarcts affiliated with vascular dementia, are important causal factors that are present even in relatively healthy elderly populations.^5–9 However, recent evidence suggests that these factors do not directly explain the majority of the variance in cognitive decline.¹⁰ This means additional factors must contribute to cognitive decline or mediate the effects of neuropathology on cognitive decline. Identifying those factors is an important step towards the alleviation of cognitive impairment in the elderly.

New findings from Hita-Yañez and colleagues in this issue of SLEEP suggest that sleep may be one of those factors.¹¹ Traditionally, disturbed sleep and circadian rhythms were described as symptoms of neurodegenerative disorders such as AD.^12–16 Hypotheses that disturbed sleep either contributes to the progression of cognitive decline, or can be used to detect patients at risk for developing cognitive disorders at a preclinical stage^11,17–24 are only beginning to be proposed. One of the unique challenges to evaluating these hypotheses is determining the appropriate populations to test these associations. Once patients have developed AD, we do not know if sleep disruption contributes to AD progression, if AD progression contributes to sleep disruption, or if a vicious cycle emerges where each exacerbates the effects of the other. To address this challenge, Hita-Yañez and colleagues¹¹ focused on a preclinical population likely to develop AD: patients with mild cognitive impairment (MCI).^25,26 In their study, objective and subjective measures of sleep were compared between healthy elderly individuals and patients with MCI. Sleep disturbances were observed in MCI patients in both objective and subjective measures. Specifically, MCI patients had more fragmented SWS and reduced REM sleep, consistent with other reports.^13,24,27 Further, REM sleep disruption was exacerbated in apolipoprotein E4 (ApoE4) carriers—a genetic marker associated with early onset AD²⁸—relative to noncarriers. Collectively, their findings suggest that even at a preclinical stage, significant sleep disturbances are present in those at risk for developing AD.¹¹ While only correlational, two clinically relevant interpretations can emerge from these data. Either sleep is particularly sensitive to dementia pathology at an early stage, or sleep disturbance is itself a contributor to disease progression. If the former is the case, then specific measures of sleep may assist in the detection of preclinical AD. If the latter is the case, sleep is one of those currently unrecognized factors contributing to cognitive decline.

Given that sleep disturbance is greater in MCI patients, symptoms of sleep disorders may be more prominent as well. To that end, a novel strength of the report by Hita-Yañez and colleagues is in their comparison of subjective measures of sleep disturbance collected at home with objective sleep measures. MCI patients had significant subjective sleep complaints, specifically reporting greater difficulty in falling asleep, staying asleep, and returning to sleep upon awakening. These findings are consistent with animal studies linking amyloid pathology to sleep fragmention.^21,27,29 This suggests that patients suffering from preclinical AD may also experience canonical symptoms of insomnia,³⁰ perhaps explaining, in part, the increased prevalence of insomnia in older adults.^31,32 Congruent with this possibility, patients with MCI exhibited another symptom of insomnia: sleep misperception.¹¹ Sleep onset latency was overestimated, and the group with MCI was less able to accurately estimate arousals, suggesting that the sleep they obtained was less restorative. In light of these findings, it is important to consider evaluating sleep in patients presenting with memory complaints, as they may be at risk for developing sleep disorders. An exciting avenue for future research would be investigating whether amyloid pathology promotes hyperarousal similar to some forms of insomnia, contributing to the increased prevalence of insomnia in later life.³³

Beyond the findings of Hita-Yañez and colleagues,¹¹ sleep disturbance may also proactively contribute to cognitive decline. This possibility remains one of the most important and yet understudied areas in sleep and aging research. A few reports have linked sleep and cognition in healthy aging^{17,22,23,34,35} and preclinical AD populations,^24,36 but little is known regarding the underlying mechanisms of this link. Is cognitive impairment exacerbated by the acceleration of neuropathology due to sleep disruption? It has been reported that sleep restriction increases β-amyloid plaque formation in rodent models of AD.²¹ Does neuropathology disrupt sleep-dependent memory? Amyloid pathology is associated with shortened and fragmented sleep.^21,27,29 It is also possible that healthy sleep may promote an independent neural resilience in the face of accumulating neuropathology, or disturbed sleep may cause independent neural dysfunction that increases susceptibility to neuropathology. Some or all of these hypotheses may be true, and future research is needed to determine exactly how sleep and its disorders are tied to cognitive decline.

Complicating matters further, sleep disturbance takes on a variety of forms, and each form may herald specific neurobehavioral and neurodegenerative consequences. For example, prospective studies have linked REM sleep behavior disorder with Parkinson disease,^37,38 insomnia with cognitive decline,³⁹ and sleep apnea with MCI and dementia.⁴⁰ Characterizing the mechanisms linking sleep disruption, neurodegeneration, and cognitive decline will pave the way for novel therapeutic targets that could minimize or delay the progression of cognitive decline. Building on these findings, known methods for SWS enhancement and sleep disorders treatment will need to be employed to aid determining whether sleep should be a viable intervention in these populations. However, if we can successfully characterize the role of sleep in cognitive decline, we may yet prove that while aging is an inevitable part of life, if healthy sleep is obtained, the negative consequences associated with it do not have to be.

CITATION

Mander BA. Disturbed sleep in preclinical cognitive impairment: cause and effect? SLEEP 2013;36(9):1275-1276.

DISCLOSURE STATEMENT

Dr. Mander has indicated no financial conflicts of interest.