Plasma pTau217 ratio predicts continuous regional brain tau accumulation in amyloid-positive early Alzheimer's disease

Abstract

Background: This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer's disease (AD).

Methods: Plasma pTau217R was measured using immunoprecipitation-mass spectrometry. Models for predicting tau PET SUVR, developed with 144 early AD individuals using [¹⁸F]MK6240, were validated in two validation sets, VS1 (98 early AD) and VS2 (47 preclinical/early AD with a different tracer, flortaucipir (Tauvid)), all amyloid-beta positive (Aβ+).

Results: The pTau217R-based model predicted tau levels up to an SUVR of 2 in multiple brain regions, effectively assessing tau status at different tau levels with receiver operating characteristic (ROC) curve areas of 0.84-0.95 in VS1 and 0.71-0.88 in VS2 (using a different tracer). It reduced PET scan needs by 65% while maintaining 95% sensitivity.

Discussion: PTau217R reliably predicts regional tau accumulation in early AD, reducing reliance on tau PET scans and broadening its clinical application.

Clinical trial registration number: NCT03887455 (ClarityAD) HIGHLIGHTS: Developed a model using plasma pTau217R to predict tau levels across brain regions. pTau217R model outperformed models based on clinical, MRI, and other blood biomarkers. The model reliably predicted tau levels exceeding tau positivity and higher thresholds. Screening with pTau217R could reduce tau PET scans by 65% at 95% sensitivity. pTau217R model aids in disease staging and monitoring in early AD.

Keywords: Tau PET; blood–based biomarkers; diagnosis; disease continuum; disease staging; patient monitoring; patient screening; prediction.

FIGURE 1

Panels A and B display the distribution of pTau217R across different amyloid and tau statuses. pTau217R levels are significantly higher in tau‐positive (T+) subjects compared to tau‐negative (T−) subjects across the training and validation sets. The mean pTau217R values show a steady and significant increase from Aβ− to Aβ+/T− to Aβ+/T+ subgroups (p < 0.0001). However, among Aβ− subjects, there is no significant difference in pTau217R between T− and T+ subjects (p = 0.315). Panels C and D illustrate distinct nonlinear patterns in the relationship between plasma pTau217R and tau PET SUVR values, as shown by the fitted spline regression curves across select cortical and Braak stage regions, respectively. Aβ, amyloid‐β; PET, positron emission tomography; SUVR, standardized uptake value ratio.

FIGURE 2

The upper limit to which tau PET SUVR can be reliably predicted in the validation set by the pTau217R‐based model is shown here for the WCGM and the MTL in panels A and B, respectively, using the approach employed in a recent publication. This upper prediction limit (red dashed line) was estimated by fitting the Richards five‐parameter logistic model to the predicted versus observed tau PET SUVR values in the validation set. The green dashed line represents the threshold for tau positivity. Graphs for additional cortical regions and the six Braak stage regions are available in Figures S3A–D and S4A–F, respectively. MTL, medial temporal lobe; PET, positron emission tomography; SUVR, standardized uptake value ratio; WCGM, whole cortical gray matter.

FIGURE 3

ROC curves and their corresponding AUROC values for predicting tau positivity and a higher threshold of 1.5 SUVR for select cortical lobes (frontal, occipital, parietal, LTL, MTL, and WCGM) and six Braak stage regions are presented in panels A through D for the VS1 and E through H for the VS2. The high AUROC values across the cortical and Braak stage regions indicate robust performance for predicting the tau status for different thresholds, which include the tau positivity threshold and a higher threshold of 1.5 SUVR. AUROC, area under ROC curve; LTL, lateral temporal lobe; MTL, medial temporal lobe; ROC, receiver operating characteristic; SUVR, standardized uptake value ratio; VS1, first validation set; VS2, second validation set; WCGM, whole corticalr gray matter.