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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Washington University School of Medicine
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:
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