Biomarkers

Area of Science:

• Neurology
• Biomarker Research
• Down Syndrome Research

Background:

• Down syndrome (DS) anti-amyloid therapy trials require PET-confirmed amyloid positivity for participant inclusion.
• Disease progression modeling is used to predict when individuals with early amyloid levels will meet trial criteria.
• Plasma pTau217 is a potential biomarker for amyloid plaque presence, but its utility in forecasting trial eligibility, especially at low amyloid levels, is under investigation.

Purpose of the Study:

• To evaluate the accuracy of plasma pTau217 in detecting amyloid positivity in individuals with DS.
• To compare disease progression modeling estimates of time-to-amyloid-positivity using plasma pTau217 versus amyloid PET.
• To assess the sensitivity of plasma pTau217 for detecting early amyloid pathology in DS.

Main Methods:

• Included 329 individuals with DS from the ABC-DS study.
• Utilized longitudinal amyloid PET (PiB or AV45) and plasma pTau217 (Lilly assay) data.
• Employed ROC analysis to determine the optimal pTau217 threshold for amyloid positivity and compared temporal estimates using generalized additive models.

Main Results:

• An optimal plasma pTau217 cutoff of 0.4778 µg/mL was identified for amyloid positivity (15-30 Centiloids).
• Plasma pTau217 showed high variability and lower accuracy (MAE=5.2 years, ρ=0.226) at lower amyloid levels (<30 CL).
• Beyond 30 CL, plasma pTau217 and PET estimates of time-to-positivity correlated well (MAE=3.5 years, ρ=0.629).

Conclusions:

• Plasma pTau217 effectively predicts amyloid-PET positivity and estimates time-to-positivity in individuals with DS with amyloid burden >30 CL.
• The assay demonstrated limited utility for estimating time-to-positivity at lower amyloid pathology levels (10-30 CL).
• The specific plasma pTau217 assay may lack the required sensitivity for early amyloid positivity detection in people with DS.