Sleep Disturbance Correlates with Cognitive Impairment Partly via Plasma p-Tau217: ADNI Cross-Sectional Evidence and P301L Mouse Mechanistic Observations

How sleep disturbances link to cognitive decline in Alzheimer’s disease (AD) via tau pathology is unclear. We explored whether sleep dysfunction worsens cognitive deficits by elevating plasma phosphorylated tau217 (p-Tau217). We combined Alzheimer’s Disease Neuroimaging Initiative (ADNI) human cohort mediation analysis with 6-week chronic sleep deprivation (SD) assays in P301L tau transgenic mice. Out of 5423 screened subjects, we included 230 participants with complete data. Clinical analyses revealed sleep disturbance independently linked to higher plasma p-Tau217 and worse cognition. Bootstrap mediation confirmed p-Tau217 partially mediated the sleep–cognition link, accounting for a 44.8% mediating effect. This pathway only existed in mild cognitive impairment (MCI) and AD patients. We also ruled out reverse causality. In mice, chronic SD triggered broad cognitive deficits without obvious stress elevation. Behavioral dysfunction was accompanied by hippocampal neuronal loss, glial overactivation, and widespread p-Tau217 hyperphosphorylation, whereas total tau showed only mild, sex-restricted upregulation. These animal observations corroborated our clinical results. In conclusion, we characterize a stage-specific correlational sleep-p-Tau217-cognition axis associated with early AD pathological changes. These findings provide preliminary translational clues linking sleep disruption to p-Tau217 dysregulation and subsequent cognitive impairment, laying a foundation for future exploration of sleep-targeted strategies for early AD intervention.