Sleepiness in Cognitively Unimpaired Older Adults Is Associated With CSF Biomarkers of Inflammation and Axonal Integrity

Abstract

IntroductionSleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer’s disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline.MethodsIn this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Aβ42, p-tau, p-tau/Aβ42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APOε4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea.ResultsHigher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001–0.016], p = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002–0.018], p = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Aβ42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001–0.012], p = 0.021) increase in the log of CSF p-tau/Aβ42.ConclusionSleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness via disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Aβ42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations.

Sleep and APOE‐ε4 have a synergistic effect on plasma biomarkers and longitudinal cognitive decline in older adults

“…The impact of SCI on future dementia is partially mediated by NfL (proportion of total effect that is mediated: 0.229). The relationships between SCI and NfL, as well as NfL and dementia, have been confirmed in several previous studies 10,45,46 . Interestingly, in the Sleep+ group, we observed that SCI fully mediated the relationship between GDS and Aβ42/40 (proportion of total effect that is mediated: 0.715).…”

“…The relationships between SCI and NfL, as well as NfL and dementia, have been confirmed in several previous studies. 10,45,46 Interestingly, in the Sleep+ group, we observed that SCI fully mediated the relationship between GDS and Aβ42/40 (proportion of total effect that is mediated: 0.715). This finding is not surprising as previous research has reported a strong negative correlation between GDS and Aβ42/40.…”

“…Furthermore, studies by Adriano et al 10 . and Carvalho et al 46 . have confirmed the potential role of NfL as a biomarker for disrupted sleep/excessive daytime sleepiness in patients with AD and its role in predicting neurodegeneration and cognitive decline.…”

“…Carvalho et al46 have confirmed the potential role of NfL as a biomarker for disrupted sleep/excessive daytime sleepiness in patients with AD and its role in predicting neurodegeneration and cognitive decline. Higher NfL levels may be associated with sleep disruption and excessive daytime sleepiness through interference with connections or damage to arousal centers.…”

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea

“…We have shown higher rates of amyloid PET accumulation in individuals without dementia with excessive daytime sleepiness 13 and higher tau PET levels in cognitively unimpaired (CU) individuals with higher risk for obstructive sleep apnea (OSA), 14 consistent with other evidence supporting a bidirectional relationship between sleep disorders and AD pathology. 15 However, we have also found an increase in CSF neurofilament light chain in CU individuals with daytime sleepiness, suggesting that sleep disturbance may be associated with underlying WM injury, 16 concerning for coexistent vascular pathology. This is particularly relevant in patients with OSA, which has been extensively associated with CVD.…”