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Groot C, Smith R, Stomrud E, Binette AP, Leuzy A, Wuestefeld A, Wisse LE, Palmqvist S, Mattsson-Carlgren N, Janelidze S, Strandberg O, Ossenkoppele R, Hansson O. Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals. Brain. 2022 Sep 9; PubMed.
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Washington University School of Medicine
This report by Groot and colleagues takes the critical step in the current AT(N) framework to suggest further classification with “P”, phosphorylated tau (p-tau). In this study, the team deeply characterized CSF p-tau217 as a representative of this proposed “P” class. They clarified that the A+P+T- group did not show faster atrophy and cognitive decline than the A+P-T-, while the A+P+T+ group showed faster atrophy and cognitive decline compared to all other groups. That supports p-tau217 as an early stage AD biomarker modulated closely with amyloid, rather than tau pathology followed by neurodegeneration as reported previously (Milà-Alomà et al., 2022).
Conceptually, I agree with the suggested framework of APT(N); however, I also make a reminder that diverse characteristics of different p-tau species are reported and different statements may be available depending on the specific p-tau species to represent the class of “P.” For instance, Barthélemy and colleagues reported that p-tau217 began with the initial increases in aggregate amyloid-β as early as two decades before the development of tau pathology in dominantly inherited AD, whereas others, like p-tau205, increase with atrophy and hypometabolism closer to symptom onset and tangles formation (Barthélemy et al., 2020). These findings have been validated in sporadic AD cases (Barthélemy et al., AAIC2022), suggesting that it is necessary to define "P" classification more in detail to consider the newly suggested framework of APT(N).
Finally, now it is obviously desirable to establish fluid biomarkers to track changes in tau pathology specifically that occur even after AD dementia onset, because the current p-tau and other biomarkers are not sufficient to cover this point. The ongoing studies to fulfill this unmet need will further refine the APT(N) framework drafted in this study by Groot et al.
References:
Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, Fagan AM, Perrin RJ, Goate AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Berman SB, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Noble J, Farlow M, Chhatwal J, Graff-Radford NR, Salloway S, Schofield PR, Masters CL, Martins RN, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. Nat Med. 2020 Mar;26(3):398-407. Epub 2020 Mar 11 PubMed.
Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, Ortiz-Romero P, Montoliu-Gaya L, Benedet AL, Karikari TK, Lantero-Rodriguez J, Vanmechelen E, Day TA, González-Escalante A, Sánchez-Benavides G, Minguillon C, Fauria K, Molinuevo JL, Dage JL, Zetterberg H, Gispert JD, Suárez-Calvet M, Blennow K. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease. Nat Med. 2022 Sep;28(9):1797-1801. Epub 2022 Aug 11 PubMed. Correction.
View all comments by Kanta HorieWashington University in St. Louis
The currently described work, along with a number of other publications in the field, clearly shows that changes in p-tau occur well before increases in tau PET. I'm hesitant, though, to suggest the field move toward adding another category. For the most part, there is a very high congruency between p-tau species and amyloid as measured with PET or CSF. Even p-tau205, which elevates later in the disease course than do p-tau231, p-tau181, or p-tau217, seems to be elevated a decade or more before tau PET. I think the only biofluid measure that has come close to capturing increases in tau PET are some of the MTBR species as published by Horie et al., 2021.
References:
Horie K, Barthélemy NR, Sato C, Bateman RJ. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain. 2021 Mar 3;144(2):515-527. PubMed. Correction.
View all comments by Brian GordonLund University
We appreciate this interesting discussion. Based on our data, CSF and plasma concentrations of p-tau217 are not simply a marker of Aβ plaques. In fact, both neuropathology-based and PET imaging-based studies have shown that fluid p-tau217 is related to both plaques and tangles to similar degrees (Mattsson-Carlgren et al., 2021). This is very different from Aβ42/Aβ40 and p-tau231, which both are mainly related to plaque pathology (Salvadó et al., 2022). Further, in human brain tissue, p-tau217 is mainly found in neurofibrillary tangles and neuropil threads, but also in granulovacuolar degeneration bodies and multi-vesicular bodies, and these brain changes correlate strongly with plasma p-tau217 levels in amyloid-positive individuals (Wennström et al., 2022). Together, these studies and others strongly suggest that p-tau217 is reflecting amyloid-induced changes in tau metabolism and aggregation, which occur subsequent to (and likely downstream of) Aβ aggregation.
From a clinical point of view, it is important to note that amyloid-positive but p-tau217-negative cases (A+P-T-) do not accumulate tau tangle pathology in the coming years as revealed with longitudinal tau-PET imaging (Groot et al., 2022). This is in contrast to those who are both amyloid-positive and p-tau217 positive, but still tau-PET-negative (A+P+T-). These cases do indeed show evidence of tau tangle accumulation in the next couple of years.
More importantly, in amyloid-positive, cognitively unimpaired cases, p-tau217 is a stronger predictor of cognitive decline over the coming four to six years than is amyloid PET, again indicating that A+P+ individuals are further along in the disease process than A+P- cases (Mattsson-Carlgren et al., unpublished data from BioFINDER-1 and WRAP studies).
In our hands, CSF concentrations of MTBR-tau243 are indeed very closely related to tau-PET. This marker holds great promise to replace tau-PET in certain situations, when one needs a measure of tau tangle pathology (T). But I am uncertain if this tau biomarker can replace p-tau217 (P) as a marker of amyloid-induced changes in tau metabolism in sporadic preclinical disease, which was our intention with the idea of using APT(N).
References:
Mattsson-Carlgren N, Janelidze S, Bateman RJ, Smith R, Stomrud E, Serrano GE, Reiman EM, Palmqvist S, Dage JL, Beach TG, Hansson O. Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau. EMBO Mol Med. 2021 Jun 7;13(6):e14022. Epub 2021 May 5 PubMed.
Salvadó G, Ossenkoppele R, Ashton NJ, Beach TG, Serrano GE, Zetterberg H, Mattsson-Carlgren N, Janelidze S, Blennow K, Hansson O. Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads. medRxiv, August 22, 2022. medRxiv
Wennström M, Janelidze S, Nilsson KP, Netherlands Brain Bank, Serrano GE, Beach TG, Dage JL, Hansson O. Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels. Acta Neuropathol Commun. 2022 Jan 6;10(1):3. PubMed.
Groot C, Smith R, Stomrud E, Binette AP, Leuzy A, Wuestefeld A, Wisse LE, Palmqvist S, Mattsson-Carlgren N, Janelidze S, Strandberg O, Ossenkoppele R, Hansson O. Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals. Brain. 2022 Sep 9; PubMed.
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