Quantitative Modelling of Amyloid-β Dynamics in Brain, CSF, and Plasma During Sleep and Wakefulness

Amyloid-beta (Aβ) accumulation in the brain is linked to Alzheimer’s disease. In healthy individuals, Aβ rises during wakefulness and is cleared during sleep, yet the effects of sleep disturbances on the Aβ dynamics are unclear. We developed a model, incorporating brain, cerebrospinal fluid (CSF), and plasma, to investigate the Aβ dynamics along the sleep-wake cycles. The model reproduces the experimentally observed 24-hour Aβ42 oscillations in CSF (660–760 pgml ^-1 ) and plasma (15–19 pgml ^-1 ) and predicts brain Aβ dynamics. Indwelling lumbar catheter data show elevated CSF Aβ42 levels on the second morning after a full night of sleep compared to first morning. The model predicts this increased level is due to repeated CSF sampling, which affects Aβ levels through pressure-mediated changes in CSF, impaired sleep-associated clearance, or their synergistic effect. These findings provide a framework for understanding Aβ regulation, highlighting sleep’s protective role and the need for non-invasive measurement approaches.

Highlights

• A quantitative three-compartment model captures 24-hour amyloid-beta dynamics across brain, CSF, and plasma during sleep-wake cycles in healthy individuals.

• The model reproduces normal sleep-wake activity of amyloid-beta in CSF and plasma, consistent with healthy physiological dynamics.

• Model predicts brain amyloid-beta concentrations, providing insights into dynamics experimentally challenging to measure.

• Experimental datasets with repeated lumbar punctures show day-to-day CSF amyloid beta accumulation, deviating from stable dynamics expected under healthy homeostasis.

• The model predicts lumbar punctures alter CSF amyloid beta levels through pressure-mediated changes in CSF, sleep-dependent glymphatic clearance, or both.