[en] BACKGROUND: Although separate lines of research indicated a moderating role of sex in both sleep-wake disruption and in the interindividual vulnerability to Alzheimer's disease (AD)-related processes, the quantification of sex differences in the interplay between sleep-wake dysregulation and AD pathology remains critically overlooked. Here, we examined sex-specific associations between circadian rest-activity patterns and AD-related pathophysiological processes across the adult lifespan.
METHODS: Ninety-two cognitively unimpaired adults (mean age = 59.85 ± 13.77 years, range = 30-85, 47 females) underwent 10 days of actigraphic recordings, and blood drawing. Standard non-parametric indices of 24-h rest-activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted from actigraphy data using the GGIR package. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β42/40 (Aβ42/40), total tau, and tau phosphorylated at threonine 181 (p-tau181) or threonine 231 (p-tau231) were measured using Single molecule array technology. Multiple linear regression models were adjusted for age, sex, education, body mass index, and actigraphic recording duration.
RESULTS: Higher IV, indicating worse 24-h rest-activity rhythm fragmentation, was associated with elevated levels of plasma NfL (t(85) = 4.26, P < 0.0001), GFAP (t(85) = 2.49, P = 0.01), and at trend level with lower Aβ42/40 ratio values (t(85) = -1.95, P = 0.054). Lower IS, reflecting less day-to-day stability in the 24-h rest-activity rhythm, was linked to elevated levels of plasma NfL (t(85) = -2.24, P = 0.03), but not with the other plasma biomarkers. Importantly, interaction models demonstrated that male participants were driving the observed relationships between IV and plasma NfL (t(84) = 4.05, P < 0.001) or GFAP (t(84) = 3.60, P < 0.001), but also revealed a male vulnerability in models testing interactions with p-tau181 (IV: t(76) = 3.71, P < 0.001; IS: t(76) = -3.30, P = 0.001) and p-tau231 (IV: t(82) = 3.28, P = 0.002). Sensitivity analyses further showed that accounting for potential confounding factors such as APOE genotype, depression, and self-reported symptoms of possible sleep apnea did not modify the observed relationships.
CONCLUSIONS: These findings suggest that the association between disrupted circadian rest-activity patterns and AD pathophysiological processes may be more evident in cognitively unimpaired males. Our results contribute to the precision medicine approach, and they have clinical implications for improved early detection and selection of at-risk individuals to be enrolled in preventive interventions.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Van Egroo, Maxime; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands. m.vanegroo@maastrichtuniversity.nl ; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. m.vanegroo@maastrichtuniversity.nl ; , UNS40 box 34, P.O. Box 616, Maastricht, 6200 MD, The Netherlands. m.vanegroo@maastrichtuniversity.nl
Beckers, Elise ; Université de Liège - ULiège > GIGA ; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands
Ashton, Nicholas J; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway ; Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, King's College London, London, Maurice, UK ; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK
Blennow, Kaj; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden ; Pitié-Salpêtrière Hospital, Paris Brain Institute, ICM, Sorbonne University, Paris, France ; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China
Zetterberg, Henrik; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden ; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK ; UK Dementia Research Institute at UCL, London, UK ; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China ; Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA
Jacobs, Heidi I L; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands ; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Language :
English
Title :
Sex differences in the relationships between 24-h rest-activity patterns and plasma markers of Alzheimer's disease pathology.
BrightFocus Foundation European Union. Marie Skłodowska-Curie Actions Maastricht Imaging Valley Swedish Research Council ADDF - Alzheimer's Drug Discovery Foundation Hjärnfonden NIH - National Institutes of Health CAF - Cure Alzheimer’s Fund Olav Thon Foundation Erling Persson Family Foundation Stiftelsen för Gamla Tjänarinnor UK DRI - UK Dementia Research Institute Alzheimer Nederland Alzheimer's Association UM - University of Maastricht
Funding text :
This study was supported by Alzheimer Nederland (#WE.03-2019-02, H.I.L.J.), Alzheimer\u2019s Association (AARG-22-920434, H.I.L.J.)), intramural funding from the Centre for Integrative Neuroscience, Maastricht University, the Netherlands, and the University of Maastricht \u2013 ULi\u00E8ge Imaging Valley (E.B.). M.V.E. is supported by BrightFocus Foundation (A20211016F) and European Union\u2019s Marie Sk\u0142odowska-Curie Actions (101109451-ADEEPSLEEP). K.B. is supported by the Swedish Research Council (#2017\u2009\u2212\u200900915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hj\u00E4rnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer\u2019s Association 2021 Zenith Award (ZEN-21-848495). H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023\u2009\u2212\u200900356; #2022\u2009\u2212\u200901018 and #2019\u201302397), the European Union\u2019s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809\u20132016862), the AD Strategic Fund and the Alzheimer\u2019s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer\u2019s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f\u00F6r Gamla Tj\u00E4narinnor, Hj\u00E4rnfonden, Sweden (#FO2022-0270), the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme \u2013 Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). H.I.L.J. is supported by NIH grants R01AG062559, R01AG06806, R01AG082006, and R21AG074220.
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