Abstract
INTRODUCTION: The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal-to-noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS: Fifty-seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS: Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non-AD tauopathies. DISCUSSION: These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non-AD tauopathies.