Cardiorespiratory Fitness Modifies Influence of Sleep Problems on Cerebrospinal Fluid Biomarkers in an At-Risk Cohort

Article type: Research Article

Authors: Law, Lena L.^{a; b; c} | Sprecher, Kate E.^{d; e; f} | Dougherty, Ryan J.^g | Edwards, Dorothy F.^{b; c; g} | Koscik, Rebecca L.^c | Gallagher, Catherine L.^{a; b; h} | Carlsson, Cynthia M.^{a; b} | Zetterberg, Henrik^{i; j; k; l} | Blennow, Kaj^{i; j} | Asthana, Sanjay^{a; b} | Sager, Mark A.^{b; c} | Hermann, Bruce P.^{b; c; h} | Johnson, Sterling C.^{a; b; c} | Cook, Dane B.^{g; m} | Bendlin, Barbara B.^{a; b; c} | Okonkwo, Ozioma C.^{a; b; c; *}

Affiliations: [a] Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [b] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [c] Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [d] Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA | [e] Wisconsin Center for Sleep Medicine and Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [f] Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA | [g] Department of Kinesiology, University of Wisconsin School of Education, Madison, WI, USA | [h] Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [i] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [j] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden | [k] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK | [l] UK Dementia Research Institute, London, UK | [m] Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA

Correspondence: [*] Correspondence to: Ozioma C. Okonkwo, PhD, Department of Medicine and Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. Tel.: +1 608 265 4479; Fax: +1 608 265 3091; E-mail: [email protected].

Abstract: Background:Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer’s disease (AD) pathophysiology, including reduced amyloid-β (Aβ) and tau pathology. However, few studies have examined CRF and sleep in the same analysis. Objective:To examine the relationship between sleep and core AD cerebrospinal fluid (CSF) biomarkers among at-risk healthy late-middle-aged adults and determine whether CRF modifies this association. Methods:Seventy-four adults (age = 64.38±5.48, 68.9% female) from the Wisconsin Registry for Alzheimer’s Prevention participated. Sleep was evaluated using the Medical Outcomes Study Sleep Scale, specifically the Sleep Problems Index I (SPI), which incorporates domains of sleep disturbance, somnolence, sleep adequacy, and shortness of breath. Higher scores indicate greater sleep problems. To assess CRF, participants underwent a graded exercise test. CSF was collected via lumbar puncture, from which Aβ42, total-tau (t-tau), and phosphorylated-tau (p-tau) were immunoassayed. Regression analyses examined the association between SPI and CSF biomarkers, and the interaction between SPI and CRF on these same biomarkers, adjusting for relevant covariates. Results:Higher SPI scores were associated with greater p-tau (p = 0.027) and higher t-tau/Aβ42 (p = 0.021) and p-tau/Aβ42 (p = 0.009) ratios. Analyses revealed significant SPI*CRF interactions for t-tau (p = 0.016), p-tau (p = 0.008), and p-tau/Aβ42 (p = 0.041); with a trend for t-tau/Aβ42 (p = 0.061). Specifically, the relationship between poorer sleep and these biomarkers was significant among less fit individuals, but not among those who were more fit. Conclusion:In a late-middle-aged at-risk cohort, CRF attenuated the association between poor sleep and levels of select CSF biomarkers. This suggests fitness may play an important role in preventing AD by protecting against pathology, even in impaired sleep.

Keywords: Alzheimer’s disease, amyloid-β protein, biomarkers, cardiorespiratory fitness, cerebrospinal fluid, sleep, tau protein

DOI: 10.3233/JAD-180291

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 111-121, 2019