Comparing the Clinical Utility and Diagnostic Performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays

Abstract

Background and objectives: Phosphorylated tau (p-tau) in CSF is considered an important biomarker in Alzheimer disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including p-tau at threonines 181 (p-tau181), 217 (p-tau217), and 231 (p-tau231). However, no studies have compared their diagnostic performance or association to β-amyloid (Aβ) and tau-PET. Understanding which p-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of p-tau181, p-tau217, and p-tau231 in CSF for AD and their association with Aβ and tau-PET.

Methods: A total of 629 participants in the Swedish BioFINDER-2 study were included (cognitively unimpaired, n = 334; Aβ-positive mild cognitive impairment, n = 84; AD dementia, n = 119; and non-AD disorders, n = 92). In addition to p-tau181 and p-tau217 measured using assays with the same detector antibodies from Eli Lilly (p-tau181_Lilly, p-tau217_Lilly) and p-tau231, we also included p-tau181 measurements from 2 commonly used assays (Innotest and Elecsys).

Results: Although all p-tau variants increased across the AD continuum, p-tau217_Lilly showed the greatest dynamic range (13-fold increase vs 1.9-5.4-fold increase for other p-tau variants for AD dementia vs non-AD). P-Tau217_Lilly showed stronger correlations with Aβ- and tau-PET (p < 0.0001). P-Tau217_Lilly exhibited higher accuracy than other p-tau variants for separating AD dementia from non-AD (area under the curve [AUC], 0.98 vs 0.88 [p < 0.0001] - 0.96 [p < 0.05]) and for identifying Aβ-PET (AUC, 0.86 vs 0.74 [p < 0.0001] and 0.83 [p < 0.001]) and tau-PET positivity (AUC, 0.94 vs 0.80-0.92, p < 0.0001). Finally, p-Tau181_Lilly generally performed better than the other p-tau181 assays (e.g., AD dementia vs non-AD, AUC, 0.96 vs 0.88 [p-tau181_Innotest] and 0.89 [p-tau181_Elecsys]; p < 0.0001).

Discussion: CSF p-tau217_Lilly seems to be more useful than other included p-tau assays in the workup of AD. Varied results across p-tau181 assays highlights the importance of anti-tau antibodies for biomarker performance.

Classification of evidence: This study provides Class II evidence that p-tau217 provides higher diagnostic accuracy for diagnosis of AD dementia than p-tau181 or p-tau231.

Figure 1. Schematic Overview of the Included Phosphorylated Tau (P-Tau) Assays

Schematic illustration of full-length tau441, including N-terminal, proline-rich region, microtubuli binding domain, and C-terminal. Anti-tau antibodies are indicated for each of the 5 included p-tau assays under the respective epitope region.

Figure 2. CSF Phosphorylated Tau (P-Tau) Slopes as a Function of β-Amyloid (Aβ) and Tau-PET Standardized Uptake Value Ratio (SUVR)

CSF p-tau levels (expressed as mean fold change relative to the mean of Aβ-negative cognitively unimpaired [CU] participants) are shown against global Aβ PET neocortical SUVR across all CU participants (A) and in Aβ-positive mild cognitive impairment (MCI) (B). Panels C and D show corresponding plots for tau-PET in all CU participants (Braak I/II) and in all Aβ-positive cognitively impaired participants (Braak III/IV) (i.e., Aβ-positive MCI and Alzheimer disease [AD] dementia combined). Generalized additive models with cubic regression splines were used to compare the slopes of CSF p-tau isoforms across different Aβ and tau-PET SUVR values. Shaded gray areas indicate 95% confidence intervals.

Figure 3. CSF Phosphorylated Tau (P-Tau) Across PET-Based Braak Stages

Levels of CSF p-tau181_Innotest (A), p-tau181_Lilly (B), p-tau181_Elecsys (C), p-tau217_Lilly (D), and p-tau231_ADx (E) are expressed relative to the mean of participants showing no abnormal tau-PET standardized uptake value ratio (SUVR) values in any of the investigated regions of interest (Braak 0, n = 437). Tau positivity in Braak stages III/VI was established using a priori cutoffs based on the mean SUVR within a given region of interest plus 2.5 SD among β-amyloid (Aβ)–negative young controls. Solid gray horizontal lines indicate age-adjusted group comparisons: Alzheimer disease (AD) dementia higher than all groups (p < 0.001); Aβ-positive mild cognitive impairment (MCI) higher than cognitively unimpaired (CU) and non-AD (p < 0.001); Aβ-positive CU higher than Aβ-negative CU and non-AD (p < 0.001). In order to facilitate comparison between p-tau measures, y-axes were scaled to the maximum fold change seen across biomarkers. AD dem. = Alzheimer disease dementia; non-AD = non-Alzheimer disease neurodegenerative disorders.

Figure 4. CSF Phosphorylated Tau (P-Tau) Across Diagnostic Groups

Levels of CSF p-tau181_Innotest (A), p-tau181_Lilly (B), p-tau181_Elecsys (C), p-tau217_Lilly (D), and p-tau231_ADx (E) are expressed relative to the mean of β-amyloid (Aβ)–negative participants (n = 253). Solid gray horizontal lines indicate age-adjusted group comparisons: Alzheimer disease (AD) dementia higher than all groups (p < 0.001); Aβ-positive mild cognitive impairment higher than cognitively unimpaired (CU) and non-AD neurodegenerative disorders (p < 0.001); Aβ-positive CU higher than Aβ-negative CU and non-AD (p < 0.001). In order to facilitate comparison between p-tau measures, y-axes were scaled to the maximum fold change seen across biomarkers. In order to facilitate comparison between p-tau measures, y-axes were scaled to the maximum fold change seen across biomarkers.

Figure 5. Receiver Operating Characteristic Plots for CSF Phosphorylated Tau (P-Tau)

Receiver operating characteristic curves are shown for the following groups: Alzheimer disease (AD) dementia vs β-amyloid (Aβ)–negative cognitively unimpaired (CU) (A), AD dementia vs non-AD disorders (B), Aβ-PET positive vs negative (C), and tau-PET positive vs negative using the Braak III/IV (D) and V/VI (E) regions of interest (ROIs). AUC = area under the receiver operating characteristic curve; CI = confidence interval.