The emergence of tau PET imaging over the last decade has enabled Alzheimer's disease (AD) researchers to examine tau pathology in vivo and more effectively characterize the disease trajectories of AD. Current tau PET analysis methods, however, typically perform inferences on large cortical ROIs and are limited in the detection of localized tau pathology that varies across subjects. Furthermore, a high-resolution MRI is required to carry out conventional tau PET analysis, which is not commonly acquired in clinical practices and may not be acquired for many elderly patients with dementia due to strong motion artifacts, claustrophobia, or certain metal implants. In this work, we propose a novel conditional diffusion model to perform MRI-free anomaly detection from tau PET imaging data. By including individualized conditions and two complementary loss maps from pseudo-healthy and pseudo-unhealthy reconstructions, our model computes an anomaly map across the entire brain area that allows simply training a support vector machine (SVM) for classifying disease severity. We train our model on ADNI subjects (n=534) and evaluate its performance on a separate dataset from the preclinical subjects of the A4 clinical trial (n=447). We demonstrate that our method outperforms baseline generative models and the conventional Z-score-based method in anomaly localization without mis-detecting off-target bindings in sub-cortical and out-of-brain areas. By classifying the A4 subjects according to their anomaly map using the SVM trained on ADNI data, we show that our method can successfully group preclinical subjects with significantly different cognitive functions, which further demonstrates the effectiveness of our method in capturing biologically relevant anomaly in tau PET imaging.
