Per Simoa, CSF p-tau205 Tracks with Tangles, Disease Progression

Most phospho-tau fluid biomarkers validated so far track more tightly with amyloid plaques than they do with tau tangles. A new study published January 6 in Acta Neuropathologica confirms that p-tau205 breaks that mold. In the cerebrospinal fluid of people in different stages of AD, this p-tau epitope flickered upward in the early days of tangle accumulation, and continued to rise in step with worsening tau pathology, neurodegeneration, and cognitive decline. So suggests a new immunoassay developed by researchers in Kaj Blennow’s lab at the University of Gothenburg, Sweden. The authors believe that this phospho-tau could serve as a disease staging biomarker. It may also fulfill a strong need in the field for a true biomarker of tangles.

  • Scientists developed immunoassays for p-tau202 and p-tau205.
  • CSF p-tau205 correlates with tangles, cognitive decline, and neurodegeneration.
  • It rises throughout the clinical stages of AD.

The findings align with recent data from researchers at Washington University in St. Louis, who used mass spectrometry to measure CSF p-tau205 and other p-tau biomarkers in two cohorts. They found that while most phospho-tau epitopes, such as p-tau217 and p-tau181, were more allegiant to amyloid PET than to tau PET, p-tau205 only moved in step with tau (Barthélemy et al., 2023). Previous work by the WashU group in people with dominantly inherited AD identified a similar pattern (Mar 2020 news).

WashU’s Nicolas Barthelemy said the new immunoassay provides further support for p-tau205’s relationship with tangles. “Importantly, this p-tau205 immunoassay would provide broader availability to clinicians for staging their patients and estimating the degree of tau pathology without tau-PET scans,” he wrote.

Co-first authors Laia Montoliu‑Gaya, Juan Lantero-Rodriguez, and colleagues developed Simoa-based immunoassays to detect tiny amounts of p-tau205, as well as a related phospho-epitope, p-tau202. These two residues are the target of the workhorse AT8 antibody, which researchers have long used to label hyperphosphorylated tau (Goedert et al., 1995 ). In a small Gothenburg-based discovery cohort, people with AD had more of both phospho-epitopes in their CSF than did normal controls, per these new immunoassays.

The researchers next tested CSF samples from 474 people across the AD spectrum, including 212 from a clinical cohort in Paris and 262 from TRIAD, a Montreal-based research cohort. In both cohorts, p-tau202 was only significantly elevated among those with an AD diagnosis, whereas p-tau205 rose in cognitively normal people with amyloidosis, bumping up further in those with MCI and AD.

The authors next categorized participants based on amyloid (A) and tangle (T) status. In the Paris cohort, this was done with core CSF biomarkers, namely Aβ42/40 for “A” and p-tau181 for “T.” In TRIAD, PET scans were used. Regardless of how amyloid and tangles were measured, p-tau202 only increased in A+T+ participants, while p-tau205 rose gradually across the continuum, from A-T- to A+T- to A+T+. Across the board, p-tau205 outperformed p-tau202 in discriminating between AT groups. Interestingly, both biomarkers climbed among a few A-T+ volunteers. This hints that they might pick up tau pathology in non-AD cases, although larger studies will be needed to find out, the authors said.

Tangle Trackers? CSF p-tau205 (left) and p-tau202 (right) correlated with different stages of amyloid- and tau-PET positivity. [Courtesy of Lantero-Rodriguez et al., Acta Neuropathologica, 2024.]

Do these p-tau epitopes track better with amyloid-PET, or tau-PET? Using scan data from the TRIAD cohort, the researchers found that while both correlated with amyloid-PET, the p-tau205 association was stronger, and it more clearly distinguished people with amyloid. However, both markers tracked more strongly with tau-PET than they did with amyloid-PET, and once again, CSF p-tau205 was more sensitive. While p-tau202 was significantly elevated only among people in the latest stage of tau accumulation—i.e., Braak stages V-VI—p-tau205 rose sequentially across the stages, from Braak 0 to VI. In statistical analyses, the researchers found that a combination of amyloid and tangles explained concentrations of both CSF markers. However, tau-PET was the strongest contributor.

Finally, the scientists investigated whether CSF p-tau202/205 reflected neurodegeneration and cognitive decline. Both biomarkers reflected lower gray-matter volume, and lower MMSE scores. However, p-tau205 tracked more strongly with both.

“Although both CSF biomarkers associated with multiple aspects of AD, p-tau205 came out as a superior, more sensitive biomarker across the board. As such, p-tau205 holds promise as a staging marker that moves in step with tau accumulation,” Lantero-Rodriguez and Montoliu‑Gaya told Alzforum.

When considered across the AD spectrum, p-tau205 may bridge the gap between amyloid-centric biomarkers p-tau231 and p-tau217, and the later-stage tau tangle marker MTBR-tau-243, Lantero-Rodriguez suggested.

To Cliff Jack of the Mayo Clinic in Rochester, Minnesota, the paper provides more evidence that p-tau205 is a useful fluid biomarker for tau deposits in AD. “Of course, p-tau205 will not provide the topographic information tau PET does, but this paper shows that it can be useful in disease staging,” he wrote. As such, Jack and other researchers recently categorized p-tau205, along with MTBR-tau-243 and tau-PET, as “T2” biomarkers, which reflect tau tangles and disease stage as part of their revised diagnostic criteria for AD (Nov 2023 conference news).

Montoliu‑Gaya noted that while p-tau217 can start to climb decades prior to symptom onset, p-tau205 might signal when symptoms are imminent. As such, it could help trialists select people in the sweet spot for intervention studies. The researchers are currently measuring p-tau205—in both CSF and plasma—in larger research cohorts.—Jessica Shugart

Comments

  1. Tau double phosphorylation at residues 202 and 205 is one of the hallmarks of brain tau aggregates and has been used over the last decades for neuropathological studies on tau aggregation using the AT8 antibody.

    In cerebrospinal fluid, multiple phosphorylated tau residues have been monitored by immunoassays, including p-tau181, p-tau231, then, more recently, p-tau217 or 235. Mass spectrometry has been used as an alternative to immunoassays for CSF p-tau measurement and, overall, a dozen phosphorylations have been reported in CSF on tau residues 111, 153, 175, 181, 199, 202, 205, 208, 212, 214, 217, 231, 235, and 396 (Barthelemy et al., 2019; Gobom et al., 2022; Therriault et al., 2022). Though mono phosphorylated p-tau202 and p-tau205 are detected in CSF, none of these techniques has been successful in detecting the 202+205 double phosphorylation in soluble tau.

    The CSF concentrations for all these phosphorylated species of p-tau typically increase in AD and associate more strongly with amyloid PET deposition than with tau PET (Barthelemy et al., 2022).  Higher p-tau can be observed at early stages of amyloid deposition, when participants are still cognitively normal, with specificity depending on the considered phosphorylated residue. CSF p-tau concentrations keep increasing at symptomatic stages. In parallel, concentration of non-phosphorylated tau (t-tau) increases. This increase is less specific than for p-tau at asymptomatic stages and more significant in participants with cognitive symptoms.

    In addition to the measures of p-tau concentrations in CSF, our group uses mass spectrometry to measure p-tau to non-phosphorylated tau ratios. This normalization allows the study of tau phosphorylation independently from variations affecting CSF tau and p-tau concentrations. We attribute these sources of variation inherent to variability among individuals but also inherent to disease-related causes that modify tau secretion from neurons, the production of CSF, and CSF protein clearance.

    P-tau/tau ratios demonstrate that most of the CSF tau-phosphorylated sites (111, 153, 181, 205, 208, 217, and 231) are abnormally hyperphosphorylated in response to amyloid pathology (Barthelemy et al., 2019; Barthelemy et al., 2022; Barthelemy et al., 2020). Thus, in AD, concentrations of these p-tau species in CSF increase more than does t-tau.

    Amongst hyperphosphorylated tau sites, p-tau205 stands out for its particular behavior. It is normal in asymptomatic people who have brain amyloid, and it increases specifically around symptom onset, when tau PET signal becomes detectable (Barthelemy et al., 2020). For this reason, p-tau205 better associates with tau PET than with amyloid PET (Barthelemy et al., 2023;  Horie et al., 2023). 

    P-tau202 is also an exception. The p-tau202/t-tau ratio in AD remains quite like that in the normal population. We have even observed slightly lower p-tau202/tau ratios in sporadic and familial AD with mild to moderate cognitive symptoms (Barthelemy et al., 2022). This suggests 202 phosphorylated tau remains partially sequestered in aggregates, where this residue is highly enriched (Horie et al., 2020). Thus, CSF p-tau202 concentration changes in concert with t-tau with no hyperphosphorylation affecting its abundance in CSF.

    The design of antibodies that bind specifically to 202 and 205 phosphorylated residues without cross-reactivity to each other has been a challenge considering the sequence homology surrounding these sites (SPG202pSPGT vs. TPG205pTPGS). This has likely restricted the study of p-tau205 to MS-based platforms as reported by our group and others (Barthelemy et al., 2020; Gobom et al., 2022; Montoliu-Gaya et al., 2023). 

    This study published by Lantero-Rodriguez et al. reports for the first time the results of two immunoassays monitoring p-tau205 and p-tau202 in CSF. Convincingly, the results support previous observations that CSF p-tau205 better associates with tau PET than with amyloid PET. The authors also report that p-tau202 concentration increases occur mostly later in AD, as we would expect for t-tau concentration.

    Importantly, the p-tau205 immunoassay would make this marker more broadly available to clinicians, who could use the unique behavior of p-tau205 to stage the disease and to estimate the degree of tau pathology without tau PET. Finally, this assay opens the door to using p-tau205 as a candidate blood-based biomarker for AD tau pathology.

    References:

    Barthélemy NR, Mallipeddi N, Moiseyev P, Sato C, Bateman RJ. Tau Phosphorylation Rates Measured by Mass Spectrometry Differ in the Intracellular Brain vs. Extracellular Cerebrospinal Fluid Compartments and Are Differentially Affected by Alzheimer's Disease. Front Aging Neurosci. 2019;11:121. Epub 2019 May 21 PubMed.

    Gobom J, Benedet AL, Mattsson-Carlgren N, Montoliu-Gaya L, Schultz N, Ashton NJ, Janelidze S, Servaes S, Sauer M, Pascoal TA, Karikari TK, Lantero-Rodriguez J, Brinkmalm G, Zetterberg H, Hansson O, Rosa-Neto P, Blennow K. Antibody-free measurement of cerebrospinal fluid tau phosphorylation across the Alzheimer's disease continuum. Mol Neurodegener. 2022 Dec 12;17(1):81. PubMed.

    Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, Servaes S, Benedet AL, Ashton NJ, Karikari TK, Lantero-Rodriguez J, Kunach P, Wang YT, Fernandez-Arias J, Massarweh G, Vitali P, Soucy JP, Saha-Chaudhuri P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P. Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging. 2022 Jun;2(6):526-535. Epub 2022 Apr 25 PubMed. Nature Aging

    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.

    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

    Horie K, Salvadó G, Barthélemy NR, Janelidze S, Li Y, He Y, Saef B, Chen CD, Jiang H, Strandberg O, Pichet Binette A, Palmqvist S, Sato C, Sachdev P, Koyama A, Gordon BA, Benzinger TL, Holtzman DM, Morris JC, Mattsson-Carlgren N, Stomrud E, Ossenkoppele R, Schindler SE, Hansson O, Bateman RJ. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease. Nat Med. 2023 Aug;29(8):1954-1963. Epub 2023 Jul 13 PubMed.

    Horie K, Barthélemy NR, Mallipeddi N, Li Y, Franklin EE, Perrin RJ, Bateman RJ, Sato C. Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain. Acta Neuropathol Commun. 2020 Aug 27;8(1):149. PubMed.

    Barthélemy NR, Toth B, Manser PT, Sanabria-Bohórquez S, Teng E, Keeley M, Bateman RJ, Weimer RM, Wildsmith KR. Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer's Disease Brain Pathology: Not All Tau Phospho-Sites are Hyperphosphorylated. J Alzheimers Dis. 2022;85(1):415-429. PubMed.

    Montoliu-Gaya L, Alosco ML, Yhang E, Tripodis Y, Sconzo D, Ally M, Grötschel L, Ashton NJ, Lantero-Rodriguez J, Sauer M, Gomes B, Nilsson J, Brinkmalm G, Sugarman MA, Aparicio HJ, Martin B, Palmisano JN, Steinberg EG, Simkin I, Turk KW, Budson AE, Au R, Farrer L, Jun GR, Kowall NW, Stern RA, Goldstein LE, Qiu WQ, Mez J, Huber BR, Alvarez VE, McKee AC, Zetterberg H, Gobom J, Stein TD, Blennow K. Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study. Acta Neuropathol. 2023 Dec 30;147(1):5. PubMed.

    View all comments by Nicolas Barthélemy

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References

News Citations

  1. Different CSF Phospho-Taus Match Distinct Changes in Brain Pathology
  2. New Alzheimer’s Diagnostic Criteria Remain ‘Research Only’

Paper Citations

  1. 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
  2. Goedert M, Jakes R, Vanmechelen E. Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neurosci Lett. 1995 Apr 21;189(3):167-9. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Lantero-Rodriguez J, Montoliu-Gaya L, Benedet AL, Vrillon A, Dumurgier J, Cognat E, Brum WS, Rahmouni N, Stevenson J, Servaes S, Therriault J, Becker B, Brinkmalm G, Snellman A, Huber H, Kvartsberg H, Ashton NJ, Zetterberg H, Paquet C, Rosa-Neto P, Blennow K. CSF p-tau205: a biomarker of tau pathology in Alzheimer's disease. Acta Neuropathol. 2024 Jan 6;147(1):12. PubMed.

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