Noise or clearance? Reframing plasma amyloid-β variability in Alzheimer's disease as a measurable clearance signal

Plasma biomarkers, and the amyloid-β 42/40 ratio in particular, are increasingly used to stage Alzheimer's disease and to stratify and monitor clinical trials, on the tacit assumption that a single measurement reflects a stable, steady-state level of pathology. A recent micro-longitudinal study that sampled plasma weekly for five weeks in people with Alzheimer's disease challenged that assumption, reporting that most participants varied by more than half in the amyloid-β 42/40 ratio over that short window. The reflexive response is to treat such movement as measurement noise to be averaged away. Here I argue that a meaningful part of it is unlikely to be noise. In healthy adults the same ratio is among the most stable plasma analytes, so instability concentrated in disease is difficult to attribute to the assay alone. Brain-to-blood clearance of amyloid-β is itself dynamic over days, rising with sleep and falling with fragmentation, apnoea, poor cerebral perfusion, autonomic dysregulation, and sedating or anticholinergic drugs. An instantaneous plasma value therefore partly reports the clearance state of the preceding night. This clearance account is kept distinct from analytical and pre-analytical variance, and from oligomeric amyloid-β dynamics, which are considered separately. The practical problem is not the variance itself but that we measure the molecule without measuring the physiological state that moves it. I propose that an inexpensive, repeatable, bedside index of that state, illustrated here with the Systemic BenBrik Geriatric Score, could be recorded alongside each plasma draw and modelled as a covariate, converting nuisance variance into interpretable signal. The prediction is falsifiable, and a validation design is outlined. This is a hypothesis, not a validated result; the illustrative index used here, the Systemic BenBrik Geriatric Score, is not a validated measure.