# Disentangling on and off-target binding in flortaucipir PET: a voxel-to-voxel P-tau, ferric iron, and MAO-B histology-to-flortaucipir PET comparison

## TL;DR

This study investigates why Flortaucipir PET scans sometimes detect signals unrelated to tau protein, comparing them with brain tissue data to better interpret the results.

## Contribution

The study introduces a voxel-to-voxel comparison method to analyze off-target Flortaucipir binding in relation to tau, iron, and MAO-B in various brain diseases.

## Key findings

- Flortaucipir signal in Alzheimer's disease moderately correlates with tau pathology but also with ferric iron and MAO-B.
- In non-AD tauopathies and FTLD-TDP-43, Flortaucipir signal correlates more with ferric iron and MAO-B than with tau.
- Off-target Flortaucipir signals are not fully explained by the studied factors, suggesting other contributors.

## Abstract

Flortaucipir PET imaging has significantly advanced our ability to visualize tau pathology in vivo. However, off-target Flortaucipir signal remains a considerable challenge for interpreting of imaging results, particularly in non-Alzheimer's tauopathies and non-tau pathologies. To better understand this off-target signal, we used an innovative voxel-to-voxel correlation approach, analyzing thousands of histology-Flortaucipir pairs from individual cases. This allowed us to quantitatively assess the relationship between Flortaucipir PET signal and three key biological factors: histological tau burden (CP-13 phospho-tau), ferric iron (Perls’ Prussian blue), and monoamine oxidase B (MAO-B). Our study included individuals with Alzheimer's disease (AD), various non-AD tauopathies, and a case of FTLD-TDP-43 type A. In AD, Flortaucipir signal showed a significant but moderate correlation with histological tau pathology, suggesting that while tau is a major contributor, other biological factors also influence Flortaucipir binding in AD. Conversely, in non-AD tauopathies and FTLD-TDP-43, correlations between Flortaucipir signal and tau pathology were weak or negligible. Instead, Flortaucipir signal correlated more strongly with ferric iron and MAO-B. However, these factors did not fully explain all the off-target signals, implying other unknown contributors are likely involved. These findings underscore the complexity of interpreting Flortaucipir PET scans. A thorough understanding of off-target binding mechanisms is crucial for improving the diagnostic accuracy of Flortaucipir PET and its specificity.

The online version contains supplementary material available at 10.1007/s00401-026-02983-x.