Tau PET and Plasma p‐tau217 as Independent and Synergistic Predictors of Clinical Progression in Early Symptomatic AD Patients With Amyloid and Tau Pathology

TL;DR

This study shows that combining blood-based p-tau217 and tau PET imaging improves prediction of clinical decline in early Alzheimer's patients.

Contribution

Demonstrates synergistic value of plasma p-tau217 and tau PET for predicting AD progression in amyloid-positive patients.

Findings

Patients with higher baseline tau PET and p-tau217 showed significant clinical worsening at Week 76.

Combining tau PET and p-tau217 provided better prognostic value than either marker alone.

Higher risk of progressing to CDR-GS MCID was observed in patients with elevated tau PET and p-tau217.

Abstract

Blood‐based biomarkers have significant potential to aid in the diagnosis of Alzheimer's disease (AD), providing a more accessible option than cerebrospinal fluid testing or positron emission tomography (PET). The objective of this study is to evaluate the prognostic value of a plasma p‐tau217 immunoassay and tau PET imaging with respect to clinical progression.

Placebo‐treated, early symptomatic AD patients (all amyloid‐positive by amyloid PET) in the TRAILBLAZER‐ALZ 2 study (NCT04437511) were analyzed. Patients (starting cohort N = 857) were split into below and above median groups based on median values of baseline flortaucipir tau PET signal evaluated by global AD‐signature region‐of‐interest standardized uptake value ratios (Tau PETlower, Tau PEThigher) and baseline plasma p‐tau217 levels (p‐tau217lower, p‐tau217higher). The following clinical measures were assessed at Week 76: least squares mean change from baseline in Clinical Dementia Rating ‐ Sum of Boxes (CDR‐SB) and integrated AD Rating Scale (iADRS). Time‐to‐event for the minimal clinically important difference in CDR Global score (CDR‐GS MCID), defined as any increase in CDR‐GS for 2 consecutive visits, was estimated using Kaplan‐Meier analyses. Hazard ratios (HR), 95% confidence intervals (CI), and p‐values were calculated using Cox proportional hazards model. These analyses are detailed in the figures.

At Week 76, significant differences compared to baseline in both CDR‐SB and iADRS were observed between patients with baseline Tau PEThigher|P‐tau217lower or Tau PEThigher|P‐tau217higher and those with baseline Tau PETlower|P‐tau217lower (p <0.001); although not statistically significant, a higher rate of clinical progression was observed in Tau PETlower|P‐tau217higher than Tau PETlower|P‐tau217lower (Figure 1). An increased risk of progressing to CDR‐GS MCID was observed in patients with baseline Tau PEThigher|P‐tau217higher (HR [95% CI]=1.9 [1.2‐3.1]; p <0.05) compared with those with baseline Tau PETlower|P‐tau217lower (Figure 2).

Patients with both higher baseline Tau PET and p‐tau217 showed a statistically significant clinical worsening at Week 76 compared with those with both lower baseline Tau PET and p‐tau217. Results suggest that, although baseline values of tau PET imaging and p‐tau217 alone predicted clinical worsening at Week 76, using both tau PET and p‐tau217 provided a better prognostic value than tau PET or p‐tau217 alone in patients with early symptomatic AD.

Figures