Development and Clinical Validation of Global Tau Severity Score in Young- and Late- Onset Alzheimer's Disease Using Florzolotau (18F) PET

Abstract

Abstract Background Tau-specific positron emission tomography (tau-PET) holds promise in distinguishing Alzheimer's disease (AD) and elucidating the spatial distribution of tau deposition. In particular, the phenotypic differences between the young-onset AD [YOAD] and late-onset AD [LOAD] likely arise from the distinct biological properties of tau proteins to their downstream pathways. This study aimed to establish a global tau severity (gTS) scale based on Florzolotau (18F) PET, a highly specific second-generation tau tracer for diagnosing AD, for standardizing tau burden quantification. Methods A total of 186 participants were enrolled and divided into a pilot group (15 cognitive unimpaired controls [CTLs] and 15 AD patients) and a validation group (27 CTLs, 67 patients with YOAD, and 62 patients with LOAD). The pilot group results were utilized to create an AD-specific tau mask and determine the optimal Florzolotau (18F) reference region based on effect size. In the validation group, cutoffs for diagnosing YOAD and LOAD using the gTS score were calculated. Regression models were used to assess the impact of amyloid centiloid, gTS score, and hippocampal volume on cognitive outcomes. Results The white matter region was determined to be the most suitable reference for Florzolotau (18F). The gTS cutoff values of 24.1 for both AD and YOAD and 34.1 for LOAD demonstrated highest diagnostic accuracy, as indicated by the area under the curve. The gTS scores significantly predicted total scores and subdomains on cognitive ability screening instruments. Cognitive-gTS curve features were found to have quadratic and linear relationships with YOAD and LOAD, respectively, illustrating the direct effect of tau pathology on cognition. Conclusions The gTS score, derived from Florzolotau (18F) PET scans, provides a robust method for assessing global tau burden. The scale reveals different cognition–tau relationships in YOAD and LOAD, indicating distinct pathological property of tau on disease progression.