Associations between objective sleep metrics and brain structure in cognitively unimpaired adults: interactions with sex and Alzheimer's biomarkers

Abstract

INTRODUCTION: Sleep disturbances are prevalent in Alzheimer's disease (AD), probably emerging during its preclinical stage. Poor subjective sleep quality is linked to reduced brain volume and cortical thickness (CTh), but associations with objective sleep measures, particularly regarding sex and AD pathology, remain unclear. METHODS: We characterized 171 cognitively unimpaired adults from the ALzheimer and FAmilies (ALFA) Sleep study using actigraphy, MRI, amyloid beta 42/40, and phosphorylated tau at threonine 181 in cerebrospinal fluid. RESULTS: Lower sleep efficiency, higher wake after sleep onset (WASO), and sleep fragmentation were associated with lower CTh in the medial temporal lobe and other regions linked with AD and sleep disruption, even after adjusting for AD biomarkers. Sex and AD biomarkers modified these associations, with longer WASO showing a stronger correlation with lower CTh in females. DISCUSSION: Disrupted sleep may reduce cortical integrity independently of AD biomarkers, suggesting alternative pathways. Females appear more vulnerable to impaired sleep, and AD pathology may exacerbate AD-related changes in CTh. Highlights: Poor sleep efficiency, increased WASO, and sleep fragmentation are associated with reduced CTh in regions vulnerable to early AD, independently of amyloid and tau pathology. In the presence of AD pathology, this relationship is altered, with A+T+ individuals exhibiting increased CTh associated with sleep disruption. Sex-specific effects suggest females are more vulnerable to sleep-related cortical thinning. These findings highlight the potential of targeting sleep as a secondary prevention strategy to preserve brain integrity and mitigate neurodegenerative processes in AD-vulnerable regions.

The ALFA+ study receives funding from ‘la Caixa’ Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer's Association, and an anonymous international charity foundation through the TriBEKa Imaging Platform project (TriBEKa‑17‑519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under Grant 2017-SGR-892. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (2022-01018 and 2019-02397), the European Union's Horizon Europe Research and Innovation Programme under Grant Agreement 101053962, Swedish State Support for Clinical Research (ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2022-0270), the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). K.B. is supported by the Swedish Research Council (2017‑00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB‑201809‑2016615); the Swedish Alzheimer Foundation (AF‑742881); Hjärnfonden, Sweden (FO2017‑0243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‑agreement (ALFGBG‑715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019‑466‑236); the National Institutes of Health (NIH), USA (Grant 1R01AG068398‑01); and the Alzheimer's Association 2021 Zenith Award (ZEN‑21‑848495). M.S.C. receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (Grant Agreement 948677), the Instituto de Salud Carlos III (PI19/00155, PI22/00456), and from the ERC under the EU's ‘la Caixa’ Foundation (ID 100010434) and from the EU's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant (847648, LCF/BQ/PR21/11840004). J.D.G. is supported by the Spanish Ministry of Science and Innovation (RYC‑2013‑13054). J.D.G. has also received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD (Grant Agreement 115952), EIT Digital (Grant 2021), and from Ministerio de Ciencia y Universidades (Grant Agreement RTI2018‑102261). G.S-B. receives funding from the Ministerio de Ciencia e Innovacion, Spanish Research Agency, PID2020-119556RA-I00. O.G.R. receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568), from Instituto de Salud Carlos III (PI19/00117), and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme IJC2020-043417-I).