Suárez-Calvet M, Karikari TK, Ashton NJ, Lantero Rodríguez J, Milà-Alomà M, Gispert JD, Salvadó G, Minguillon C, Fauria K, Shekari M, Grau-Rivera O, Arenaza-Urquijo EM, Sala-Vila A, Sánchez-Benavides G, González-de-Echávarri JM, Kollmorgen G, Stoops E, Vanmechelen E, Zetterberg H, Blennow K, Molinuevo JL, ALFA Study. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected. EMBO Mol Med. 2020 Dec 7;12(12):e12921. Epub 2020 Nov 10 PubMed.

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Comments

  1. Congratulations to Randy Bateman and his Washington University colleagues for the initial development of this assay and to Joel Braunstein and his C2N colleagues for doing the work needed to introduce its use in the clinical setting! It is an important accomplishment and, I believe, just the beginning when it comes to the use of blood-based biomarkers in the clinical setting.

    The development of a CLIA-certified blood test to help characterize the presence or absence of amyloid plaques and return information to clinical providers, patients, and families in the clinical setting is an important landmark. It is my hope that we will see other assays, including plasma p-tau217, follow in the footsteps of this effort and provide additional value to those in the research, treatment development, and clinical setting.

    Like any tool, there is more work to do to help to fulfill its promise in the clinical setting, including helping the field find the optimal ways to communicate information, extend the approach to make it widely used and informative in the primary care setting, and leverage the information in ways that will have the greatest value for providers, patients, and families, before and after amyloid-modifying and other treatments become available.

    View all comments by Eric M. Reiman

  2. I think this is a truly exciting development for AD diagnostics! We now need to develop appropriate use criteria to avoid misuse and misinterpretation of new blood tests for diagnosis of Alzheimer’s disease, similar to what has already been done for CSF AD biomarkers and amyloid PET imaging. I would be hesitant to use blood-based AD biomarkers outside memory clinics before i) prospective studies have been performed in primary care settings, and ii) primary care physicians have received adequate training in how to interpret the results.

    Plasma p-tau assays are probably one to three years behind when it comes to implementation into the clinical practice, but very intense efforts are ongoing. Personally, I think plasma p-tau217 and p-tau181 are very well-suited for identification of AD in individuals with MCI or dementia, but combinations of several blood-based markers are most probably need for reliable detection of preclinical AD.

    If a disease-modifying therapy will be approved for clinical use, then the need for blood-based biomarkers of detection of prodromal AD and mild AD dementia will increase substantially.

    View all comments by Oskar Hansson

  3. Suárez-Calvet et al. report the promising performance of novel p-tau assays in cerebrospinal fluid to detect early changes of tau phosphorylation due to amyloid pathology. They monitored a new combination of antibodies capturing different lengths (N-ter or mid-domain) and phosphorylated residues (181, 217, and 231). Notably, their results confirm early changes of CSF tau phosphorylation in cognitively normal amyloid-positive participants as previously published for p-tau181 and p-tau217. The authors suggest p-tau231 significantly increases at the preclinical stage. Consistently, they report good correlation among p-tau levels measured at T217, T181 and T231.

    Threonine231 is located after the main CSF truncation reported on residue 224 (Cicognola et al., 2019). Capturing CSF p-tau231 with a mid-domain antibody, as performed in this study, would recover a relatively low abundant non-truncated tau fragment including the T231 residue. So, p-tau231 is likely less abundant than p-tau181 and p-tau217 and more difficult to detect without a sensitive assay. Of note, p-tau181, p-tau217, and p-tau231, along with p-tau202, are the phosphorylated species that are most enriched in AD brain tau aggregates (Horie et al., 2020). Though these species are increased in preclinical AD, corresponding brain enrichment could impact their levels in CSF once tau pathology is prominent and potentially cause them to decrease at symptomatic stage.

    These sites are part of the residues monitored by the immunoprecipitation mass spectrometry assay we developed at the Bateman lab that measures tau phosphorylation occupancy, or p-tau/tau ratio (Barthélemy et al., 2019). P-tau231 is currently under investigation in the DIAN cohort and our internal data confirms high correlation of this site with p-tau217. P-tau217 in DIAN becomes abnormal more than 20 years before the emergence of clinical symptoms (Barthélemy et al., 2020). Using our mass spectrometry method, we reported similar phosphorylation changes in a group of residues including T111, T153, T181, T217, and T231 (Wildsmith et al., ADPD conference 2020). It is important to note some other phosphorylated sites, such as S199, S202, or T175, are not significantly hyperphosphorylated in AD CSF tau. This finding supports site-specific modifications of tau phosphorylation and would predict different diagnostic efficacy of a CSF p-tau assay depending on the considered site.

    Finally, I found particularly interesting the greater accuracy observed for N-ter p-tau 181 over mid p-tau181 to detect amyloidosis. This suggests phosphorylation might be different depending on the tau truncated fragment considered.

    References:

    Cicognola C, Brinkmalm G, Wahlgren J, Portelius E, Gobom J, Cullen NC, Hansson O, Parnetti L, Constantinescu R, Wildsmith K, Chen HH, Beach TG, Lashley T, Zetterberg H, Blennow K, Höglund K. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease. Acta Neuropathol. 2019 Feb;137(2):279-296. Epub 2018 Dec 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, 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.

    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.

    View all comments by Nicolas Barthélemy

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