Non‐linear associations between sleep duration and plasma p‐tau181 in the Framingham Heart Study

INTRODUCTION: Both short and long sleep duration have been associated with Alzheimer's disease (AD) risk, yet the nature of the non-linear associations between sleep quantity and blood-based biomarkers of AD and neurodegeneration remains understudied. METHODS: Among 2410 Framingham Heart Study participants (mean age: 70.0 ± 8.45 years; 55.2% female), we examined associations between self-reported sleep duration and plasma phosphorylated tau (p-tau)181, total tau, neurofilament light chain, and glial fibrillary acidic protein using restricted cubic splines (RCS) and categorical comparisons (≤ 6, > 6-< 9 reference; ≥ 9 hours). RESULTS: RCS revealed non-linear associations between sleep duration and p-tau181 (overall p = 0.005; non-linearity p = 0.002), with higher levels at ≥ 8.5 hours, after adjusting for age, sex, apolipoprotein E ε4 genotype, sleep apnea, depression, and kidney function. Categorical comparisons showed no association in adjusted models. DISCUSSION: Sleep duration exhibits robust non-linear associations with p-tau181. Findings underscore the importance of non-linear modeling in relating sleep to blood-based biomarkers. Longitudinal studies are needed to clarify temporal relationships and mechanistic pathways.