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. 2024 Jun;20(6):4020-4031.
doi: 10.1002/alz.13802. Epub 2024 May 1.

Sleep-wake behavior, perceived fatigability, and cognitive reserve in older adults

Nancy Kerner  1   2 , Terry E Goldberg  1   2   3 , Hannah R Cohen  2 , Julia G Phillips  2 , Daniel E Cohen  2 , Howard Andrews  1   2   4 , Gregory Pelton  1   2   5 , Davangere P Devanand  1   2   5   6
Affiliations

Sleep-wake behavior, perceived fatigability, and cognitive reserve in older adults

Nancy Kerner et al. Alzheimers Dement. 2024 Jun.

Abstract

Introduction: The effects of sleep-wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR).

Methods: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis.

Results: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep-related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93).

Discussion: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below-mean CR. Therefore, improving sleep-wake regulation and leisure activities may protect against fatigability and cognitive decline.

Highlights: Clinical fatigue and fatigability cannot be alleviated by rest. Clinical fatigability disrupts daily activities during preclinical Alzheimer's. High cognitive reserve mitigates sleep-wake disturbance effects. High cognitive reserve attenuates clinical fatigability effects on daily functioning. Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain.

Keywords: Alzheimer's disease; cognitive ability; cognitive reserve; fatigue; leisure activities; older adults; sleep; sleep fragmentation; sleep–wake behavior; sleep–wake dysregulation; sleep–wake misalignment.

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Conflict of interest statement

Dr. Kerner receives support from Columbia University's Clinical and Translational Research (CTSA) and NIH/NIA. Drs. Goldberg, Qin, Andrews, Pelton, and Devanand receive support from the NIH/NIA. All authors have no conflict of interest to declare. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
The proposed moderated mediation model. This moderated mediation model tested the indirect effect of sleep‐related impairment (SRI; independent variable) on cognitive abilities (dependent variable) through the mediator fatigability, with the indirect effect being moderated by cognitive reserve (CR). The full model is comprised of two subregression models. The first‐stage model entails regressing fatigability (mediator) onto SRI, CR (at low [<−1 SD, path a1], mean [SD = 0, path a2], and high [>+1 SD, path a3] values of CR), and their interactions (SRI × CR). The second‐stage model entails regressing cognitive abilities onto SRI and fatigability simultaneously.
FIGURE 2
FIGURE 2
Effect of sleep‐related impairment on fatigability moderated by cognitive reserve. The illustrations represent the moderation effect of cognitive reserve on the relationship between sleep‐related impairment and fatigability at low (−1 SD), mean (0 SD), and high (+1 SD) levels of cognitive reserve in (A) patients with amnestic mild cognitive impairment and (B) cognitively normal healthy controls.
FIGURE 3
FIGURE 3
Connectome between the Sleep–Fatigability paradigm and the Cognitive Reserve (CR) framework. The results of this study supported our Sleep–Fatigability paradigm which is also consistent with the literature, in which (1) untreated chronic and persistent sleep–wake dysregulation could progress to sleep‐related impairment with cognitive transition from cognitive normal to amnestic mild cognitive impairment; (2) sleep‐related impairment with altered rest/activity rhythms is associated with Alzheimer's pathology in the brain; and (3) persistent fatigue that cannot be relieved with rest is a manifestation of neuroinflammation associated with beta‐amyloid and tau pathology in amnestic mild cognitive impairment and abnormal structures in the brain (eg, white matter hyperintensities in Alzheimer's disease).
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