Associations between sleep disturbance and cerebrospinal fluid Aβ, and shared proteomic signatures in Alzheimer's disease

INTRODUCTION: Sleep disturbance is increasingly recognized as a risk factor for Alzheimer's disease (AD), but longitudinal clinical evidence linking sleep behaviors to cerebrospinal fluid (CSF) amyloid beta (Aβ) dynamics and related proteomic signatures remains limited. METHODS: We analyzed 1205 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine associations between sleep disturbance, CSF Aβ42 level, and cognition. To prioritize molecular candidates associated with these phenotypes, we integrated CSF proteomics with weighted gene co-expression network analysis (WGCNA) and two-sample Mendelian randomization (MR). RESULTS: Baseline sleep disturbance was associated with a faster rate of longitudinal CSF Aβ42 decline. WGCNA identified a protein module associated with sleep disturbance and Aβ42, within which MR supported effects of sleep disturbance on multiple proteins. Among these, interferon γ-inducible protein 16 is a candidate link between sleep disturbance and Aβ pathology. DISCUSSION: Our findings suggest that sleep disturbance accelerates Aβ pathology, and implicate IFI16-related pathway as a link between disrupted sleep and AD progression.