Background. Alterations in tau protein levels and its phosphorylated form have been described in post-mortem samples of sporadic and familial ALS. Furthermore, it has been suggested that CSF tau may provide a viable biomarker of disease given that alterations in tau and pTau:tau ratio have been reported in ALS CSF. However, it is still unclear whether alterations in CSF tau may serve as biomarker for ALS.
Objectives. To determine whether there are novel genetic variants in tau and whether CSF tau levels are altered in ALS.
Results. We identified specific and unique ALS genetic variants in MAPT through the ALS Knowledge Portal and Project MinE data sets. Furthermore, we assessed tau and phosphorylated tau at T181 (pTau-T181) in CSF samples from 40 ALS patients and 10 healthy controls using Quanterix Simoa assays. The analysis revealed no change in tau or pTau-T181 in ALS CSF, while there was a decrease in pTau-T181:tau ratio, as previously reported. Importantly, tau levels were increased in bulbar-onset ALS patients, while pTau-T181:tau was decreased in both bulbar- and limb-onset ALS patients. While CSF tau levels were inversely correlated with the revised ALS functional rating scale (ALSFRS-R), pTau-T181:tau ratio positively correlated with the ALSFRS-R. Accordingly, there was an increase in the rate of ALSFRS-R decline per month associated with increases in tau levels as well as decreases in pTau-T181:tau ratio. Lastly, our preliminary analysis of plasma samples from 9 ALS and 9 healthy controls using the same Quanterix assays demonstrated an increase in plasma tau levels in ALS.
Conclusion. Our findings unveiled novel ALS specific variants in MAPT that may act as disease modifiers and provide additional support for the use of pTau-T181:tau ratio as a potential biomarker for ALS.
Acknowledgements. T.P. was supported by an award from the Judith and Jean Pape Adams Charitable Foundation and Byrne Family Endowed Fellowship in ALS Research.