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Barthélemy NR, Saef B, Li Y, Gordon BA, He Y, Horie K, Stomrud E, Salvadó G, Janelidze S, Sato C, Ovod V, Henson RL, Fagan AM, Benzinger TL, Xiong C, Morris JC, Hansson O, Bateman RJ, Schindler SE. CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer's disease. https://doi.org/10.1038/s43587-023-00380-7 PubMed. Nature Aging
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University of Pittsburgh
This is a very well-conducted and comprehensive study (of more than 20 tau measures) comparing CSF markers with AD pathophysiology measured by PET. This CSF study aligns with recent blood literature, suggesting that p-tau assays strongly correlate with and may represent both Aβ- and tau PET.
They add that CSF tau217 and 205 occupancies (phosphorylated/non-phosphorylated) are more closely related to PET than simple concentrations. This is a great advantage of the MS technique in that it allows simultaneous measurements of markers, increasing the reliability of ratios. On the other hand, most other platforms will likely be unable to accurately measure occupancy, and it adds a layer of work to MS assessment. Thus, a trade-off between the magnitude of improvement and caveats will play a role in future utility.
On the impact of the results on the ATN scheme, I don't think there are any major implications right now. CSF p-tau has already been added as a marker of tau pathology and if no epitopes other than 181 were mentioned it is likely because there was not much data on them at the time. I don't think the scheme intended to focus on 181. Also, I do not think that p-tau biomarkers should be added as a proxy for Aβ in canonical research biomarker schemes such as ATN, because they do not represent the same biological process, and this could lead to potentially incorrect assumptions cascading through studies relying on the schema.
Regarding clinical application, it seems clear from the results that CSF p-tau217 occupancy outperforms CSF p-tau181 and could also outperform CSF Aβ to identify AD. A recent study showed a mismatch between CSF Aβ and p-tau181, demonstrating, in postmortem data, a greater sensitivity of CSF Aβ to autopsy-confirmed AD (Vromen et al., 2023). Further similar studies using the new p-tau assays anchored in postmortem data would provide valuable information to ascertain the additive performance of these new high-performance assays to identify AD.
References:
Vromen EM, de Boer SC, Teunissen CE, Rozemuller A, Sieben A, Bjerke M, Alzheimer’s Disease Neuroimaging Initiative, Visser PJ, Bouwman FH, Engelborghs S, Tijms BM. Biomarker A+T-: is this Alzheimer's disease or not? A combined CSF and pathology study. Brain. 2022 May 2; PubMed.
View all comments by Tharick PascoalVU University Medical Center
This is a very interesting study by Barthélemy et al., in which several non-phosphorylated and phosphorylated tau species in the CSF were compared head-to-head. An important strength of the study design is that they were all simultaneously measured with mass spectrometry, which means there are no different antibodies and assay components affecting the comparison of the tau species.
The authors found that p-tau217/tau217 ratio associated stronger with amyloid PET status than did Aβ42/Aβ40. The surprise was CSF p-tau205/tau205, which correlated very strongly with tau PET, but interestingly, this CSF measure was not so strongly correlated with amyloid PET.
Should we revisit the ATN criteria already, and select p-tau217/tau217 as an “A” biomarker and CSF p-tau205/tau205 as a “T” biomarker? CSF and blood studies consistently show that p-tau217 might be the supreme biomarker, for both A and T. It might be time to start implementing this biomarker in clinical practice. I think it is too early to dismiss Aβ42/Aβ40 and p-tau181, but p-tau217 and perhaps p-tau205/tau205 could be add-ons to the diagnostic panel. Data is still accumulating, and performance of these new tau biomarkers should first be extensively tested in real-world settings. Also, robust (immuno)assays on high-throughput methodologies with a steady chain of supply should be in place.
View all comments by Inge VerberkMake a Comment
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