Sleep-related changes in astrocytic biomarkers are modulated by APOE e4 genotype in cognitively unimpaired adults

Abstract

Astrocytes are key regulators of sleep and neuroinflammatory responses. However, the relationship between objective sleep parameters and astrocytic fluid biomarkers in cognitively unimpaired individuals remains unclear. We examined how sleep architecture relates to astrocytic, neuroaxonal and Alzheimer’s disease-related fluid biomarkers in cognitively unimpaired adults, and whether age, sex and APOE e4 moderate these associations. This cross-sectional study included 51 cognitively unimpaired participants from the Sant Pau Initiative on Neurodegeneration cohort. One-night in-lab polysomnography was used to quantify sleep architecture, fragmentation, slow-wave activity, and respiratory parameters. CSF biomarkers included glial fibrillary acidic protein (GFAP), chitinase-like-3 protein 1 (YKL-40), Aß42, Aß40, pTau181, and tTau; plasma biomarkers included GFAP and neurofilament light chain (NfL). Associations were analyzed using Spearman correlations, multiple linear regression, and moderation models, adjusting for age, sex, body mass index, APOE e4 status, and sleep apnea. Lighter and more fragmented sleep, characterized by longer N1 duration, increased wake after sleep onset, frequent stage transitions, and elevated cortical arousal, was associated with higher CSF YKL-40, Aß40, pTau181 and tTau (rho = 0.32 to 0.62, all p<0.05). In contrast, deeper, more consolidated sleep, indicated by longer total time of sleep, greater N3 duration, and higher slow-wave activity, was associated with lower CSF GFAP and YKL-40 (rho = -0.35 to -0.44, all p<0.05). These associations remained significant in adjusted regression models. Plasma GFAP and NfL exhibited an inverse profile, with positive associations with deeper sleep (ß: 0.16 to 0.18, p < 0.05) and negative associations with lighter sleep stages (ß: –0.23 to –0.29, p < 0.01). REM sleep was also associated with astrocytic fluid biomarkers, with negative correlations for CSF and plasma GFAP (rho = -0.49 and rho = -0.28, respectively, all p<0.05), while in regression models REM duration remained a negative predictor of plasma GFAP (ß = -0.23, p = 0.003) and a positive predictor of CSF YKL-40 (ß = 0.12, p = 0.037). Notably, APOE e4 consistently moderated associations between sleep and CSF YKL-40 and GFAP, while age and sex influenced plasma GFAP and CSF YKL-40, respectively (all p<0.05). In cognitively unimpaired adults, sleep architecture is differentially associated with central and peripheral biomarkers of astrocytic activation, neuroaxonal integrity and Alzheimer’s disease-related proteins. These findings support the importance of considering sleep as a key factor in the early pathophysiology of neurodegenerative disease.

The Sant Pau Initiative on Neurodegeneration cohort received funding from Instituto de Salud Carlos III, through the Fondo de Investigación Sanitaria (FIS) (PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI20/00836, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) program (Program 1, Alzheimer Disease to A.L.), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, ‘Una manera de hacer Europa’. The Sant Pau Initiative on Neurodegeneration cohort was also supported by the National Institutes of Health (National Institutes of Health grants 1R01AG056850-01A1; R21AG056974 and R01AG061566), by Departament de Recerca i Universitats, Generalitat de Catalunya (2021 SGR 00979, SLT006/17/125, SLT006/17/119, SLT002/16/408), Fundació la Marató de TV3 grants 20141210, 044412 and 20142610, a grant from the Fundació Bancaria La Caixa to I.R.-B. (Down Alzheimer Barcelona Neuroimaging Initiative project), Fundació Catalana Síndrome de Down and Fundació Víctor Grífols i Lucas. Horizon 21 Consortium is partly funded by Fondation Jérôme Lejeune. N.Z. was supported by Instituto de Salud Carlos III through the Río Hortega Fellowship ‘CM21/00113’ and co-funded by the European Union. J.A. was supported by Instituto de Salud Carlos III through the Río Hortega Fellowship ‘CM21/00243’ and co-funded by the European Union. I.R.-B. was supported by Instituto de Salud Carlos III through the Río Hortega Fellowship ‘CM22/00052’ and co-funded by the European Union.

Postprint (published version)