Substantial levels of tau are found in the blood of humans and they were significantly lower in plasma of AD patients compared with cognitively normal controls. Based on our unpublished data, the circulating levels of tau in elderly normal controls are 2-3 times greater than encountered in the CSF.
A possible mechanism for reduced total tau in AD blood would depend on the origin of the peptide deposited in the brain. Animal studies of brain injury suggest that circulating tau emanates from central neurons [25
]. If the tau depositing in the AD brain is overproduced there, the most likely mechanism to explain the current data could be reduced clearance of excess central tau to the blood. This would be similar to findings for GDNF where increased levels are found in AD CSF compared to control, but serum levels are significantly lower than found compared to the same control population [35
]. Regardless of the mechanism, changing total tau levels in an easily accessible tissue (blood) may constitute a useful biomarker in following the progression of AD or the benefit of medications in a RCT.
The forgoing is supported by the observation that as cognitive performance declines so do circulating total tau levels. We found a highly significant correlation between reduced performance on the MMSE and Rey’s AVLT and decreased circulating total tau levels. On the one hand, the latter correlations may be an artifact of combining the three groups since according to our cross-sectional data (), tau varies among the groups and it is well known that the neuropsychological tests vary among the groups. On the other hand, the window of change possible within the control and MCI populations may be sufficiently narrow for the clinical scores (i.e., the range for the MMSE may be only 3-5 points) to correlate to circulating tau levels and therefore it would be necessary to combine the populations to observe the widest range of possible cognitive performances.
Our pilot longitudinal studies indicate that there are stable circulating tau levels in AD and MCI patients remaining AD or MCI, although there is a sight, but significant, age-related increase in circulating tau among individuals maintaining a cognitive control status. This could support the premise that tau levels rise during an individual’s life and that in MCI and AD circulating tau may begin entering the brain thus facilitating NFT formation [34
]. Longitudinal studies are underway which may be able to confirm the possibility that as an individual makes the transition from cognitive control to MCI and thereafter to AD, that circulating tau levels follow the decrease in cognitive performance in an individual.
Our tissue type and deterioration studies suggested that there is no identifiable tau in human sera employing our methods. We suggest that this might be due to collateral metabolism associated with the clotting cascade, or clot formation, or both. The fact that aged plasma contains less tau than freshly thawed sample suggest that there may also be Ca++ independent tau proteolysis distinct from collateral metabolism (the clotting cascade).
Overall the data suggest that changes in plasma total tau levels may provide a new avenue of identifying the onset of MCI and thereafter AD, thus allowing the ability to follow the disease from beginning to end. Future studies could confirm this hypothesis.