A paper entitled 'Staging tau pathology with tau PET in Alzheimer’s disease: a longitudinal study' by Chen et al. wrote "We did not observe a significant difference between the high stages (stage 3 and stage 4). A potential interpretation is that while tau continues accumulation reflected by PET tau, CSF p-tau seems to reach a plateau later in the disease"
The references they cited state "this may be in part because P-tau seems to plateau later in the disease [14] while the tau PET signal continues to increase [124]."
However, no mechanism is elucidated.
Some mechanisms that come to mind is that there could be a saturation and improper clearance into the CSF... almost as if there is a maximum/capacity of CSF clearance.
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They also found a similar flatline between early Braak stages. Potentially, tau may require to reach a threshold before CSF clearance takes place. But again, no mechanism is given.
The mechanism behind the observed phenomenon of CSF tau reaching a plateau while tau PET signal continues to increase in late stages of Alzheimer's disease is not yet fully understood. However, there are several possible explanations that have been proposed, although more research is needed to confirm these hypotheses. Here are a few potential mechanisms that could contribute to this pattern:
1. Saturation of clearance mechanisms: It's possible that there is a saturation of the clearance mechanisms responsible for removing tau from the brain into the cerebrospinal fluid (CSF). Tau is released from neurons and can be cleared through various pathways, including perivascular drainage and glymphatic system. If these clearance mechanisms become overwhelmed or compromised, they may reach a maximum capacity, leading to a plateau in CSF tau levels despite ongoing accumulation in the brain.
2. Sequestration or aggregation of tau in the brain: Tau protein can undergo pathological changes, such as aggregation into neurofibrillary tangles, which are a hallmark of Alzheimer's disease. It's possible that as the disease progresses, tau becomes sequestered or trapped within these aggregates in the brain, reducing its release into the CSF. This sequestration could lead to a discrepancy between brain tau levels detected by PET imaging and CSF tau levels.
3. Differential kinetics of tau species: Tau exists in various isoforms and phosphorylation states, and different species of tau may have different rates of accumulation, clearance, or release into the CSF. It's possible that the tau species detected by PET imaging might continue to increase due to ongoing aggregation or production, while the specific phosphorylated tau species measured in the CSF reaches a plateau at later disease stages.
4. Regional variations in tau pathology: The pattern of tau pathology in Alzheimer's disease is known to exhibit regional variability, with some brain regions being more affected than others. It's possible that the brain regions where tau PET signal is measured continue to accumulate tau at a faster rate compared to the regions sampled for CSF, leading to the observed discrepancy.
These are just some potential mechanisms that could contribute to the observed pattern of CSF tau plateauing while tau PET signal continues to increase. Further research is needed to elucidate the underlying mechanisms and clarify the relationship between CSF tau and tau PET measurements in Alzheimer's disease.