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<p>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&amp;231) and at T217 and T231 (p-tau217&amp;231). Subsequently, we measured CSF and plasma p-tau181&amp;231, p-tau217&amp;231, p-tau181, p-tau217, and p-tau231 levels in two cohorts across the AD continuum and in frontotemporal dementia (FTD) patients (discovery <i>n</i> = 55, validation <i>n</i> = 118). CSF and plasma p-tau217&amp;231, p-tau181, p-tau217, and p-tau231 and CSF, but not plasma, p-tau181&amp;231 were significantly elevated in all AD continuum groups vs. Neurological Disease Control group. Notably, plasma p-tau217&amp;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月2日

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  • Anna L. Wojdała,
  • Giovanni Bellomo,
  • Lorenzo Gaetani,
  • Charlotte E. Teunissen,
  • Lucilla Parnetti,
  • Davide Chiasserini

摘要

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.