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.