Novel tau biomarkers phosphorylated at T181, T217 or T231 rise with subtle changes in Aβ pathology (2020)
Figure 6

Figure 6. Trajectories of the p-tau biomarkers in preclinical Alzheimer.

The graphs represent the z-scores changes of each CSF biomarker as a function of CSF Aβ42/40 ratio (as proxy of disease progression) using a robust local weighted regression method. The z-scores were calculated using the mean and the SD of each CSF biomarker in the A-T- group as a reference. The solid lines depict the trajectory of each CSF biomarker. The dashed lines depict the trajectories of the plasma biomarkers. The vertical black dashed line indicates the CSF Aβ42/40 cutoff for A+. Note that the CSF p-tau biomarkers reach the 2 z-scores (depicted with an horizontal dashed line) with the following sequence: Mid-p-tau231, N-p-tau181, N-p-tau217, Mid-p-tau181 and t-tau. Abbreviations: CSF, cerebrospinal fluid; Mid, mid-region; NfL, Neurofilament light; N, N-terminal; p-tau, phosphorylated tau; t-tau, total tau.

Tables:

Table 1. Participants' characteristics and biomarkers by Aβ status group

Total

(n = 381)

A-

(n = 250, 65.6%)

A+

(n = 131, 34.4%)

Participants were classified as Aβ-negative (A-) or Aβ-positive (A+) as defined by the CSF Aβ42/40 ratio.

Data are expressed as mean (M) and standard deviation (SD) or number of participants (n) and percentage (%), as appropriate. A t-test was used to compared age, education, MMSE, and Centiloids between Aβ status groups and Pearson's Chi-square to compare sex, APOE-ε4 and Aβ PET visual read positivity frequency between Aβ status groups. All biomarkers were compared with a one-way ANCOVA adjusted by age and sex. The P-values indicated in the last column refer to the Aβ status group effect. *Significant differences.

‡Aβ PET was available in 331 participants and, among them, two did not have visual read assessment.

Abbreviations: Aβ42, amyloid-β 42; Aβ40, amyloid-β 40; CSF, cerebrospinal fluid; Mid, mid-region; MMSE, Mini-Mental State Examination; N, N-terminal; NfL, neurofilament; p-tau, phosphorylated tau; t-tau, total tau; PET, positron emission tomography; VR, visual read.

Table 2. Association of p-tau biomarkers and Aβ biomarker (either CSF Aβ42/40 or Aβ PET Centiloid scale) stratifying by Aβ status.

(n = 250)

(n = 131)

'Aβ42/40 x

Aβ status'

interaction

(n = 287)

(n = 42)

'Aβ PET

x

+0.475

(0.056)

For each p-tau biomarker we computed the linear regression standardized coefficients (β) and standard errors (SE) as a function of a Aβ pathology biomarker (either CSF Aβ42/40 or Aβ PET Centiloid scale). The analyses were performed after stratifying for Aβ-negative (A-) and Aβ-positive (A+) groups, as defined by CSF Aβ42/40 ratio or Aβ PET visual read, respectively. We report the eta-squared (eta2) as a measure of the effect size. We also computed the P-value for the interaction term 'Aβ biomarker x Aβ status'. All analyses were adjusted by age and sex. *Significant differences.

Among the 331 participants with Aβ PET, two did not have visual read assessment.

Abbreviations: CSF, cerebrospinal fluid; Mid, mid-region; N, N-terminal; PET, positron emission tomography; p-tau, phosphorylated tau.

Table 3. ROC analyses to discriminate cognitively unimpaired Aβ-positive from Aβ-negative individuals

CSF Aβ42/40

(A-: 250; A+: 131)

Aβ PET visual read

(A-: 287; A+: 42)

Aβ PET CL12

(A-: 278; A+: 53)

ROC analyses to test whether each p-tau biomarker discriminates between Aβ-positive (A+) and Aβ-negative individuals (A-), as defined by the CSF Aβ42/40 ratio, Aβ PET visual read or Aβ PET using a cutoff of CL12. We also included CSF t-tau and plasma NfL for comparison. Aβ PET was performed in 331 participants and Centiloid scale was available in all of them; two participants did not have visual read assessment.

AUCs differences were tested using the DeLong test. The significant differences were:

1P < 0.001 compared to CSF Mid-p-tau181

2P < 0.01 compared to CSF N-p-tau181

3P < 0.05 compared to CSF Mid-p-tau181

4P < 0.001 compared to CSF N-p-tau181

5P < 0.001 compared to CSF N-p-tau217

6P < 0.001 compared to CSF Mid-p-tau231

7P < 0.01 compared to CSF Mid-p-tau181

8P < 0.01 compared to CSF t-tau

9P < 0.05 compared to CSF t-tau

10P < 0.05 compared to CSF N-p-tau181

11P < 0.05 compared to plasma N-p-tau181

The exact P-values are shown in Appendix Table S1.

Abbreviations: Aβ42, amyloid-β 42; Aβ40, amyloid-β 40; AUC, area under the curve; CI, confidence interval; CL, Centiloid; CSF, cerebrospinal fluid; Mid, mid-region; N, N-terminal; NfL, neurofilament; p-tau, phosphorylated tau; t-tau, total tau; PET, positron emission tomography.

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