Plasma Biomarkers for Neocortical Tau Burden

Area of Science:

• Neuroscience
• Biomarker Discovery
• Alzheimer Disease Research

Background:

• Phosphorylated tau-217 (p-tau217) is a plasma biomarker for Alzheimer disease (AD) amyloid pathology but has limitations in identifying advanced neocortical tau burden.
• Accurate tau pathology assessment is crucial for implementing anti-amyloid therapies and developing anti-tau interventions.
• Improved biofluid biomarkers for tau staging can enhance patient stratification for clinical care and therapeutic trials.

Purpose of the Study:

• To develop and validate a multiprotein plasma panel to enhance the identification of neocortical tau pathology beyond p-tau217.
• To improve the accuracy of non-invasive tau staging for Alzheimer disease.

Main Methods:

• A multicenter cohort study involving 560 participants across the Alzheimer disease spectrum.
• Plasma protein concentrations were measured using a Nucleic Linked Immuno-Sandwich Assay central nervous system panel.
• Advanced tau pathology was defined by tau positron emission tomography (PET) uptake in Braak stages V and VI.

Main Results:

• A 7-protein panel was identified that significantly improved the prediction of advanced tau pathology (Braak stages V-VI) compared to p-tau217 alone.
• The multiprotein panel showed improved performance (AUC, 0.92-0.94) versus p-tau217 (AUC, 0.86-0.88) in both discovery and validation cohorts.
• This panel reduced the proportion of individuals in the intermediate-risk range by 14.7% to 21.0% in the validation cohort.

Conclusions:

• Including additional plasma proteins significantly enhances the prediction of advanced tau pathology in amyloid-positive individuals.
• A multiprotein plasma biomarker approach offers a viable and scalable alternative to tau PET staging.
• This advancement can optimize patient selection for clinical trials and improve Alzheimer disease management.