α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau

Technical Summary: α-Synuclein Seed Amplification Status Modifies the Relationship Between Plasma p-tau217, Amyloid and Fibrillar Tau

Problem Statement
Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a robust biomarker sufficient for the biological diagnosis of Alzheimer's disease (AD). However, a significant proportion of patients with AD pathology also carry co-pathology in the form of α-synuclein aggregation, detectable via cerebrospinal fluid (CSF) seed amplification assay (αSynSAA). Previous research indicates that αSynSAA positivity is associated with greater amyloid burden and, when conditioned on amyloid, with higher downstream tau measures (CSF p-tau181/Aβ40 ratio and tau PET). It remains unknown whether this "displacement" of the amyloid-tau relationship is detectable in plasma p-tau217 levels. Specifically, there is a clinical concern that α-synuclein seeding might artifactually inflate plasma p-tau217 independent of AD pathology burden, potentially leading to false-positive diagnoses if a single diagnostic threshold is applied across populations with and without co-pathology.

Methodology
The authors conducted a cross-sectional analysis using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The study focused on 193 participants with concurrent plasma p-tau217, CSF biomarkers, amyloid PET, and tau PET data (33 αSynSAA-positive and 160 αSynSAA-negative). Robustness checks were performed in larger samples referenced to CSF (n=286) and amyloid PET (n=246).

• Biomarkers:
  • Plasma p-tau217: Measured via Fujirebio Lumipulse assay.
  • αSynSAA: Performed on CSF by Amprion Clinical Laboratory, classifying samples as Type 1 (Lewy body profile) detected or not detected.
  • Reference Standards: Amyloid burden (Amyloid PET Centiloids), CSF amyloid positivity (p-tau181/Aβ42 ratio), and fibrillar tau burden (Tau PET SUVR).
• Statistical Approach:
  • Generalized Additive Models (GAMs) were employed to model the relationship between plasma p-tau217 and reference measures, adjusting for age, sex, APOE ε4 status, and cognitive stage.
  • The study tested for shape differences (interaction) between αSynSAA groups and estimated constant proportional differences.
  • Objective 1: Quantified the difference in plasma p-tau217 by seeding status at equivalent levels of amyloid, CSF ratio, and tau PET, and determined which measure attenuated this difference most.
  • Objective 2: Modeled fibrillar tau against amyloid and plasma p-tau217 to determine if αSynSAA+ individuals carry more tau at a given amyloid burden and if a given plasma p-tau217 level corresponds to the same tau burden in both groups.
  • Objective 3: Performed a counterfactual analysis where the estimated seeding-associated increment was removed from αSynSAA+ participants' plasma values to test if this correction improved agreement with reference standards.

Key Results

1. Elevation of Plasma p-tau217 in αSynSAA+ Individuals: At equivalent levels of amyloid PET burden (Centiloids) and CSF p-tau181/Aβ42 ratio, αSynSAA-positive participants exhibited significantly higher plasma p-tau217 levels (27.3% and 22.9% higher, respectively). However, when referenced to Tau PET (fibrillar tau), this difference was not statistically significant (12.1% higher, p=0.313).
2. Attenuation by Fibrillar Tau: Adjustment for Tau PET attenuated the association between αSynSAA status and plasma p-tau217 by 55.4%, a greater reduction than that observed with the CSF ratio (31.1%) or amyloid PET (25.4%). This suggests that the elevated plasma p-tau217 in αSynSAA+ individuals is largely explained by a higher burden of fibrillar tau.
3. Amyloid-Tau Relationship: The relationship between amyloid burden and fibrillar tau was steeper in αSynSAA-positive participants (p=0.047), confirming that seeding displaces the amyloid-tau trajectory.
4. Calibration of Plasma p-tau217 to Tau: Crucially, a given plasma p-tau217 concentration corresponded to the same fibrillar tau burden in both αSynSAA+ and αSynSAA- groups (2.5% difference, p=0.347), with no evidence of shape differences.
5. Counterfactual Classification: Removing the estimated seeding-associated increment from plasma values did not improve diagnostic agreement with reference standards. Instead, accuracy modestly decreased (e.g., from 93.9% to 92.4% against the CSF ratio), driven entirely by a loss in sensitivity. This indicates that the "excess" p-tau217 is not noise but reflects biological reality.

Significance and Claims
The paper concludes that while plasma p-tau217 is elevated in individuals with α-synuclein co-pathology at equivalent amyloid burdens, this elevation is biologically driven by an increased fibrillar tau burden rather than an α-synuclein-specific artifact. The study provides evidence that:

• The displacement of the amyloid-tau relationship observed in CSF and PET is detectable in plasma.
• The elevation in plasma p-tau217 in αSynSAA+ patients reflects true AD pathology (specifically higher fibrillar tau) rather than a false-positive signal.
• Consequently, a plasma p-tau217 result should not be down-weighted or discounted in patients with concomitant Lewy-related pathology. The authors argue that when plasma and amyloid confirmatory tests disagree in such patients, the data favor the interpretation that the amyloid measure lags the tau process, rather than the plasma measure being erroneous.

The authors maintain a modest tone, noting that the cross-sectional design limits causal inference and that the counterfactual analysis is exploratory due to sample size constraints. They emphasize that while the difference is real, it does not appear to compromise diagnostic precision in the studied cohort, though replication in earlier disease stages and diverse populations is warranted.