Immunoassay detection of multiphosphorylated tau proteoforms as cerebrospinal fluid and plasma Alzheimer’s disease biomarkers

Anna L. Wojdała (), Giovanni Bellomo, Lorenzo Gaetani, Charlotte E. Teunissen, Lucilla Parnetti () and Davide Chiasserini ()
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Anna L. Wojdała: University of Perugia
Giovanni Bellomo: University of Perugia
Lorenzo Gaetani: University of Perugia
Charlotte E. Teunissen: Amsterdam UMC
Lucilla Parnetti: University of Perugia
Davide Chiasserini: University of Perugia

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Different forms of phosphorylated tau (p-tau) have shown strong potential as Alzheimer’s disease (AD) biomarkers in both cerebrospinal fluid (CSF) and plasma. We hypothesized that p-tau proteoforms simultaneously phosphorylated at two different sites may have an increased diagnostic value compared with tau phosphorylated at a single site. Here, we developed two immunoassays detecting CSF and plasma tau simultaneously phosphorylated at both T181 and T231 (p-tau181&231) and at T217 and T231 (p-tau217&231). Subsequently, we measured CSF and plasma p-tau181&231, p-tau217&231, p-tau181, p-tau217, and p-tau231 levels in two cohorts across the AD continuum and in frontotemporal dementia (FTD) patients (discovery n = 55, validation n = 118). CSF and plasma p-tau217&231, p-tau181, p-tau217, and p-tau231 and CSF, but not plasma, p-tau181&231 were significantly elevated in all AD continuum groups vs. Neurological Disease Control group. Notably, plasma p-tau217&231 consistently showed an improved diagnostic performance compared with single-site phosphorylation assays – p-tau217 or p-tau231. The differences observed between CSF and plasma measurements suggest matrix-specific protein processing, underscoring the need for further research on the dynamics of tau phosphorylation pattern along the AD continuum.

Date: 2025
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DOI: 10.1038/s41467-024-54878-8

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