Head‐to‐head comparison of clinical performance of CSF phospho‐tau T181 and T217 biomarkers for Alzheimer's disease diagnosis

Abstract

Introduction Phosphorylated tau (p‐tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N‐terminal and mid‐region p‐tau181 and p‐tau217 fragments are available, but head‐to‐head comparison in clinical settings is lacking. Methods N‐terminal‐directed p‐tau217 (N‐p‐tau217), N‐terminal‐directed p‐tau181 (N‐p‐tau181), and standard mid‐region p‐tau181 (Mid‐p‐tau181) biomarkers in CSF were evaluated in three cohorts (n = 503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ). Results CSF N‐p‐tau217 and N‐p‐tau181 had better concordance (88.2%) than either with Mid‐p‐tau181 (79.7%–82.7%). N‐p‐tau217 and N‐p‐tau181 were significantly increased in early mild cognitive impairment (MCI)‐AD (A+T–N–) without changes in Mid‐p‐tau181 until AD‐dementia. N‐p‐tau217 and N‐p‐tau181 identified Aβ pathophysiology (area under the curve [AUC] = 94.8%–97.1%) and distinguished MCI‐AD from non‐AD MCI (AUC = 82.6%–90.5%) signficantly better than Mid‐p‐tau181 (AUC = 91.2% and 70.6%, respectively). P‐tau biomarkers equally differentiated AD from non‐AD dementia (AUC = 99.1%–99.8%). Discussion N‐p‐tau217 and N‐p‐tau181 could improve diagnostic accuracy in prodromal‐AD and clinical trial recruitment as both identify Aβ pathophysiology and differentiate early MCI‐AD better than Mid‐p‐tau181.

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…To date, there have been twelve independent data reports on plasma p-tau181 and two on plasma p-tau217. Yet, the limited evidence available may suggest some superiority of plasma p-tau217 over plasma p-tau181 [82], which is in line with CSF comparisons of the same biomarkers [92,93,117]. However, a biomarker comparison using the same detector antibody in sandwich immunoassay format has yet to be performed, and therefore it cannot be determined if the observed superiority is either assay or epitope dependent.…”

“…Tatebe et al [76] developed a p-tau181 assay by substituting the detection antibody in the Simoa™ Tau 2.0 total tau kit for a p-tau181-specific monoclonal antibody. Karikari et al [79,93] developed novel p-tau181 and p-tau217 assays targeting p-tau forms that also contain the N-terminal amino acid 6-18 epitope. Similarly, the Eli Lilly-developed p-tau181 and p-tau217 are located N-terminally to the p-tau sites [56].…”

“…Similarly, the Eli Lilly-developed p-tau181 and p-tau217 are located N-terminally to the p-tau sites [56]. Although each of the assays was primarily developed for use in blood, they are equally suitable for use in CSF [75,92,93]. By contrast, a p-tau assay that uses the same phosphorylationspecific antibody for both capture and detection (IMR method) thus exclusively targeting phosphorylation at threonine-181 irrespective of the fragment(s) on which this occurs [126] is increased not only in AD but also in other neurogenerative disorders [89].…”

“…A breakthrough discovery in the mid-1990s demonstrated that AD patients had increased levels of CSF p-tau, which was not found in other neurological diseases [48]. Later studies have since confirmed that CSF p-tau181 can be used to differentiate AD from other dementias, such as frontotemporal dementia (FTD) and dementia with Lewy bodies [91][92][93]. Recently, five studies have shown that CSF p-tau217 perform somewhat better than CSF p-tau181 when differentiating AD from non-AD diseases [92][93][94][95][96].…”

Ultrasensitive assays for detection of plasma tau and phosphorylated tau 181 in Alzheimer’s disease: a systematic review and meta-analysis

“…The loss of normal functions and the gain of toxic functions of Tau have been linked with the pathogenesis of AD [2][3][4][5][6][7]. Mounting evidence has suggested that the cerebrospinal fluid (CSF) levels of tau and phosphorylated tau are linearly associated with symptom severity of AD [8][9][10][11], suggesting tau as a promising biomarker for early diagnosis and prognostic prediction. However, clinical application of CSF biomarkers has been hindered by high cost, invasiveness, and side effects of lumbar punctures, such as positional headache [12].…”