Chronic sleep loss impairs the brain’s nightly verdict on which synaptic configurations survive. The glymphatic system performs an active triage during sleep, tagging extracellular waste for removal while sparing functional networks. Simultaneously, intracellular autophagy degrades damaged proteins and organelles. Both pathways peak during rest, yet most interventions treat them as independent. Crocetin, a carotenoid from saffron, robustly activates the STK11/LKB1‑AMPK axis, driving ATG5/7/12 expression and LC3B‑II flux in neurons【https://pmc.ncbi.nlm.nih.gov/articles/PMC8632093/】. Its pharmacokinetic profile shows brain Tmax at ~1 h and a half‑life of ~3.1 h after oral dosing【https://pmc.ncbi.nlm.nih.gov/articles/PMC8632093/】, aligning neatly with the early‑sleep window when aquaporin‑4 polarization surges and CSF influx accelerates【https://gethealthspan.com/science/article/glymphatic-system-autophagy-neurodegenerative-disease-prevention】.

We hypothesize that administering crocetin 30 minutes before bedtime couples autophagy induction with glymphatic flow, converting the two clearance mechanisms into a coordinated detoxification surge. In this coupled state, autophagosomes engulf intracellular Aβ oligomers and phosphorylated tau fragments, while the glymphatic conduit simultaneously clears extracellular plaques and soluble oligomers that have been shed from membranes. The temporal overlap should reduce the total burden of toxic species more effectively than either pathway alone, thereby improving the fidelity of synaptic triage.

Testable predictions: (1) Mice receiving crocetin at ZT12 (lights‑off) will show a >2‑fold increase in hippocampal LC3B‑II and a concurrent rise in CSF‑influx tracer accumulation compared with vehicle or crocetin given at ZT0. (2) This combined treatment will lower both intracellular (immunostained neuronal p‑tau) and extracellular (Thioflavin‑S plaque) AD pathology by ≥40 % after 4 weeks, whereas mismatched timing yields no additive benefit. (3) Electrophysiological LTP measurements will reveal rescued synaptic strength only in the pre‑sleep cohort, linking molecular clearance to functional preservation.

Falsifiability rests on the expectation that if crocetin’s autophagy boost does not amplify glymphatic tracer influx or does not further diminish pathology beyond autophagy‑only controls, the coupling hypothesis fails. Conversely, a positive result would redefine sleep‑linked brain detox as a pharmacologically gatable process, opening chronotherapeutic avenues for neurodegenerative disease.