Sleep-related changes in astrocytic biomarkers are modulated by APOE e4 genotype in cognitively unimpaired adults.
Por:
Zhu N, Altuna M, Arranz J, Rodriguez-Baz Í, Sanchez-Saudinós MB, Videla L, Valldeneu S, Carrera-Vega M, Romero-Lafuente S, Fortea J, Lleó A, Giménez S and Alcolea D
Publicada:
7 nov 2025
Ahead of Print:
7 nov 2025
Resumen:
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 analysed using Spearman correlations, multiple linear regression, and moderation models, adjusting for age, sex, body mass index, APOE e4 status and sleep apnoea. 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 (? = 0.32-0.62, 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 (? = -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: 0.16-0.18, P < 0.05) and negative associations with lighter sleep stages (ß: -0.23 to -0.29, P < 0.01). Rapid eye movement (REM) sleep was also associated with astrocytic fluid biomarkers, with negative correlations for CSF and plasma GFAP (? = -0.49 and ? = -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.
Filiaciones:
Zhu N:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
Altuna M:
CITA-Alzheimer Foundation, Donostia-San Sebastián 20009, Spain
Osakidetza, Organización Sanitaria Integrada (OSI), Debabarrena 20850, Spain
Arranz J:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
Rodriguez-Baz Í:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Sanchez-Saudinós MB:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Videla L:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona 08041, Spain
Valldeneu S:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Carrera-Vega M:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Romero-Lafuente S:
Automatic Control Department (ESAII) and Institute for Research and Innovation in Health (IRIS), Universitat Politècnica de Catalunya-BarcelonaTech (UPC), BarcelonaTech (UPC), Barcelona 08005, Spain
Fortea J:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona 08041, Spain
Lleó A:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
Giménez S:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Multidisciplinary Sleep Unit, Respiratory Department, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Alcolea D:
Sant Pau Memory Unit, Department of Neurology, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid 28029, Spain
Open Access
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