Biomarkers.

Area of Science:

• Neurology
• Biomarker Discovery
• Alzheimer's Disease Research

Background:

• Alzheimer's disease (AD) pathophysiology and biomarker research are advancing.
• Amyloid PET is a standard diagnostic tool and outcome measure in AD trials, but it is expensive and resource-intensive.
• Plasma phosphorylated tau (pTau) is being investigated as a more accessible biomarker for AD.

Purpose of the Study:

• To evaluate the accuracy and sensitivity of plasma pTau (pT217, pT181) in predicting clinical outcomes and disease progression in Alzheimer's disease (AD) trials.
• To compare the utility of plasma pTau biomarkers against traditional amyloid PET imaging.
• To assess the potential of plasma pTau as a primary outcome measure in early-phase drug development.

Main Methods:

• Analysis of published data from anti-amyloid monoclonal antibody (mAb) studies.
• Calculation of group-level Pearson correlations between plasma pT217/pT181 treatment effects and clinical outcomes.
• Comparison of plasma pTau correlations with amyloid PET correlations.
• Power calculations to simulate proof-of-concept study designs and assess sample size requirements.

Main Results:

• Plasma pT217 and pT181 demonstrated group-level correlations with clinical outcomes comparable to amyloid PET.
• Effect sizes (Cohen's d) for plasma pT217/pT181 were larger than those for standard clinical outcome assessments (ADAS-Cog, ADCS-ADL, CDR-SB).
• Plasma pT217/pT181 showed 3-fold greater sensitivity to disease progression, enabling comparable power with one-ninth the sample size.

Conclusions:

• Plasma pTau biomarkers (pT217, pT181) offer a reliable, cost-effective, and accessible alternative to amyloid PET for predicting clinical outcomes in AD.
• These biomarkers exhibit larger effect sizes and higher sensitivity for disease progression compared to current clinical measures.
• Plasma pTau biomarkers can facilitate smaller, more efficient early-phase clinical trials for Alzheimer's disease drug development.