My understanding is that they are saying that the cause is being awake. I don't understand the modeling they are doing, but they are saying that the time curve

My understanding is that they are saying that the cause is being awake. I don't understand the modeling they are doing, but they are saying that the time curve of the concentration should be different if clearance was changing at night, so they think there is little change in clearance but only in production. They mention one alternative that would also fit the data: "In order for decreased glymphatic clearance during sleep deprivation to increase soluble CSF Aβ, a decrease in irreversible losses (e.g. to the bloodstream or lymphatics) due to prolonged overnight waking would have to be perfectly matched by an increase in Aβ clearance to CSF. This is plausible but unlikely and not identifiable from the current data." They say "The SILK kinetics results unequivocally show that glymphatic clearance alone, without compensation from other clearance mechanisms, would be ineffective in protecting the brain from AD because overall clearance rates are not changing. Glymphatic clearance may potentially contribute to the protective effects of sleep against AD, but changes in production rate seem to be the necessary and critical factor." Also worth noting that they were unable to test if changes in slow wave sleep made a difference because sodium oxybate didn't actually increase slow wave sleep in that group vs normal sleepers. It does sound like this contradicts previous research, at least: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880190/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880190/ They do cite that paper but do not have a detailed analysis of how their results could be consistant or are contradictory to what that study found. In that study radioactive amyloid beta was directly injected into mice and then how much of it was left was observed after varying amounts of time later and in sleeping vs. awake vs anesthetized. Maybe newly produced amyloid beta could be cleared instead of the radiolabeled amyloid beta or maybe the injected amyloid beta had different clearanace properties than naturally generated amyloid beta, but I don't know if either of those are plausable. Maybe they are just contradictory results. If it is correct that the production changes are what makes the difference, I wonder why that is the case considering the much larger fluid exchange that happens at night. Also I wonder if some of the other similar substances that cause problems if they accumulate too much have a similar issue. Maybe stuff that can be cleared at high rate is easier to get rid of with relatively little sleep and stuff that can't is more likely to cause trouble over time.