As increasing evidence suggests that a disrupted sleep-wake cycle can drive the development of Alzheimer disease and other neurocognitive disorders via β-amyloid accumulation, a new study finds that the association between β-amyloid accumulation and cognitive impairment can be mediated by sleep disruption even after the onset of cognitive decline.
As increasing evidence suggests that a disrupted sleep-wake cycle can drive the development of Alzheimer disease (AD) and other neurocognitive disorders via β-amyloid accumulation, a new study finds that the association between β-amyloid accumulation and cognitive impairment can be mediated by sleep disruption even after the onset of cognitive decline.
The study, published in JAMA Network Open, cites prior literature indicating a bidirectional relationship between sleep dysfunction and β-amyloid deposition, but notes that most of these studies have examined individuals with normal cognition. The investigators sought to study the associations among β-amyloid abnormalities, sleep quality, and cognitive function in patients 65 years or older with a diagnosis of mild cognitive impairment (MCI) or dementia who received treatment at a large referral center for cognitive disorders and AD.
Cognition was assessed using the 30-point Mini-Mental State Examination (MMSE), and sleep quality was measured by 2 validated sleep questionnaires—a nighttime sleep quality survey and a modified Epworth Daytime Sleepiness Scale—that participants completed on their own or with a family member or caregiver. Patients with MMSE scores less than 24, indicating cognitive impairment, were required to have at least 1 family member or caregiver present to confirm the accuracy of their responses. Participants also underwent positron emission tomography imaging of the brain areas commonly associated with β-amyloid deposits.
Of the 52 patients included in the study analyses, the mean (SD) age was 76.6 (7.4) years, and 51.9% were female. Imaging analysis revealed that 34 participants (65.4%) had elevated levels of β-amyloid in the brain, with the highest levels found in the precuneus, anterior cingulate gyrus, and brainstem compared with other brain regions.
There was a significant association between daytime sleepiness scores and β-amyloid deposition in the brainstem (P = .02) but not in other brain regions or in the brain overall. MMSE performance was not associated with daytime sleepiness, and the weak inverse association between MMSE performance and β-amyloid deposition was no longer significant after controlling for age.
The investigators found that nocturnal awakenings were significantly associated with both precuneus β-amyloid deposition and poor MMSE performance (P = .01 for both) before and after adjustment for age, sex, race/ethnicity, hours of nighttime sleep, sleep apnea, sleep medication use, and dementia medication use. These relationships were also found in a subgroup of 34 participants with AD or MCI; nocturnal awakenings were positively associated with precuneus β-amyloid deposition (P = .001) and negatively associated with MMSE score (P = .002), but β-amyloid deposition and MMSE performance were not significantly associated.
Because β-amyloid deposition was more strongly associated with nocturnal awakenings than with poor MMSE performance, the study authors “hypothesized that [β-amyloid] did not have a direct association with poor cognition but instead was associated with cognitive impairment indirectly via nocturnal awakenings as an intermediary.” Their mediation analyses confirmed that nocturnal awakenings mediated the association between β-amyloid and cognitive impairment as measured by poor MMSE performance.
They noted the significance of the findings of different sleep behaviors associated with β-amyloid levels in various brain regions. For example, nocturnal awakenings were associated with β-amyloid deposition in the precuneus, which helps facilitate slow-wave sleep, whereas daytime sleepiness was associated with β-amyloid deposition in the brainstem, which plays an important role in attention and arousal.
The findings could hold valuable insights for clinical trials of antiamyloid immunotherapy treatments for cognitive disorders, which may need to target both β-amyloid deposits and sleep dysfunction in order to successfully improve cognition.
“Future investigation of the mechanism underlying this indirect association may be crucial for improved understanding of cognitive decline in disorders associated with [β-amyloid] accumulation,” the study authors concluded.
You JC, Jones E, Cross DE, et al. Association of β-amyloid burden with sleep dysfunction and cognitive impairment in elderly individuals with cognitive disorders. JAMA Netw Open. 2019;2(10):e1913383. doi: 10.1001/jamanetworkopen.2019.13383.