Effects of acute sleep deprivation on individuals across different APOE genotypes: a randomized controlled trial...

Sleep is crucial for the clearance of metabolic waste products. Sleep deprivation leads to the accumulation of amyloid-β (Aβ) and tau proteins, which may be mediated by impaired glymphatic clearance, thereby contributing to the hallmark pathologies of Alzheimer's disease (AD). The apolipoprotein E (APOE) gene, particularly the APOE ε4 allele, is a major genetic risk factor for AD and is also closely associated with sleep. Notably, the interaction between poor sleep and APOE ε4 may further enhance AD risk. However, prior studies have reported inconsistent effects of sleep deprivation on AD related biomarkers, and clinical studies stratified by APOE genotype are lacking. This study aims to investigate the effects of 24-h acute sleep deprivation on plasma AD biomarkers and to assess APOE genotype-dependent responses.

This prospective, randomized open-label, blinded-endpoint trial plans to enroll 60 healthy young adults. Participants will be stratified by APOE genotype into three groups at a 1:1:1 ratio: APOE ε3/ε3 homozygotes, APOE ε4 carriers (ε3/ε4 and ε4/ε4 genotypes), and APOE ε2 carriers (ε2/ε3 and ε2/ε2 genotypes). Within each genotype stratum, participants will be randomly assigned in a 1:1 ratio to either the 24-h acute sleep deprivation group or the normal sleep group. The primary outcome is the change in plasma Aβ₄₂ levels from baseline to day 1 after randomization. Secondary outcomes include changes from baseline to day 1 after randomization in plasma levels of the following biomarkers: Aβ₄₀, total tau (t-tau), phosphorylated tau-181 (p-tau181), phosphorylated tau-217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Additionally, the following ratios will be assessed: Aβ₄₂/Aβ₄₀, t-tau/Aβ₄₂, p-tau181/Aβ₄₂, and p-tau217/Aβ₄₂. Changes in neuropsychiatric and cognitive assessment will also be evaluated, including scores on the Fatigue Scale-14 (FS-14), the Positive and Negative Affect Schedule (PANAS), and performance on the N-back tasks. Exploratory outcomes include changes in plasma proteomics and metabolomics, as well as positron emission tomography/magnetic resonance imaging (PET/MRI) measures.

This study serves as the first randomized controlled trial (RCT) to explore the potential influence of acute sleep deprivation on plasma AD biomarkers across different APOE genotypes, with the largest sample size among current RCTs on sleep deprivation. This trial is expected to generate critical evidence elucidating the impact of 24-h acute sleep deprivation on the pathophysiology of AD and to inform the development of future sleep-focused preventive interventions.

ClinicalTrials.gov, identifier NCT07085754.