Sleep drives an active triage of neural components rather than a simple housekeeping sweep[https://pubmed.ncbi.nlm.nih.gov/41325105/]. We propose that the glymphatic system does not flush all interstitial solutes indiscriminately; instead, it preferentially removes proteins that carry a specific ubiquitin‑like tag deposited by neuronal activity‑dependent E3 ligases during waking[https://pmc.ncbi.nlm.nih.gov/articles/PMC2665998/]. This tag, which we call the "sleep‑clearance mark" (SCM), is recognized by perivascular astrocytic aquaporin‑4 channels that facilitate its entry into CSF flow. Arterial pulsatility provides the mechanical energy that sweeps SCM‑tagged species toward venous outlets, while low‑pulsatility conditions allow tagged proteins to linger and seed pathological aggregates[https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf453/8362252]. Consequently, chronic sleep loss or arterial stiffening does not merely let waste accumulate; it blocks the nightly verdict on which synaptic architectures merit preservation, leading to the gradual dominance of maladaptive connections[https://doi.org/10.1002/ana.24271][https://pubmed.ncbi.nlm.nih.gov/34049040/][https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0193397].

Testable predictions follow. First, pharmacological enhancement of arterial pulse amplitude—using a short‑acting vasodilator such as hydralazine administered during the early night—should rescue glymphatic clearance of SCM‑tagged tau in mice subjected to fragmented sleep, measurable by reduced intracellular tau aggregates in hippocampal sections. Second, genetic knockout of the putative neuronal E3 ligase that deposits SCM should abolish the sleep‑dependent decline in tagged proteins, leaving total interstitial protein levels unchanged but eliminating the selective loss seen in wild‑type controls. Third, in humans, simultaneous measurement of pulse wave velocity, overnight CSF flow (via phase‑contrast MRI), and PET ligands for SCM‑modified amyloid‑β should reveal a mediation pathway where arterial stiffness predicts reduced CSF influx, which in turn predicts higher cerebral burden of the modified peptide, independent of total amyloid load.

If these experiments show that boosting arterial pulsatility restores selective clearance without increasing total sleep time, the hypothesis gains support. Conversely, if clearance of SCM‑tagged species remains unaffected by pulse manipulation or if tagging does not predict nightly loss, the model would be falsified.