Plasma p-Tau217 and SPECT-Based eZIS in Mild Cognitive Impairment: Concordance Analysis with Validation in an Amyloid PET Sub-Cohort

Abstract

(1) Background/Objectives: Blood-based biomarkers have emerged as practical tools for identifying Alzheimer’s disease (AD) pathology in patients with mild cognitive impairment (MCI). Among them, plasma phosphorylated Tau217 (p-Tau217) demonstrates strong associations with cerebral amyloid deposition. In parallel, the easy Z-score Imaging System (eZIS), a quantitative brain perfusion SPECT analysis tool, has been widely used to detect characteristic AD-related hypoperfusion patterns. Although both measures reflect distinct AD processes, the relationship between plasma p-Tau217 and eZIS in MCI remains unclear. (2) Methods: This retrospective study included 62 patients with MCI who underwent plasma p-Tau217 testing and brain perfusion SPECT with eZIS analysis. Associations between plasma p-Tau217 and the three eZIS indices (severity, extent, and ratio) were evaluated. Exploratory subgroup analyses were performed using a previously reported plasma p-Tau217 threshold of 0.63 pg/mL. In addition, a validation sub-cohort of 21 participants who underwent plasma p-Tau217 testing, eZIS, and amyloid PET was analyzed to assess concordance with cerebral amyloid pathology. (3) Results: Among the three eZIS indices, severity demonstrated the highest sensitivity relative to elevated plasma p-Tau217 levels. However, all eZIS indices showed limited discriminative performance. Optimal eZIS cutoff values derived from the present cohort were higher than previously reported thresholds. In the amyloid PET-validated sub-cohort, plasma p-Tau217 demonstrated closer concordance with amyloid positivity than any individual eZIS parameter. The reduced performance of eZIS appeared to be associated with advanced age, substantial vascular burden, white matter lesions, and cerebral atrophy. (4) Conclusions: Plasma p-Tau217 showed a stronger association with cerebral amyloid pathology than eZIS indices in this elderly MCI cohort. Nevertheless, eZIS may provide complementary information regarding downstream neurodegenerative and cerebrovascular processes that are not directly captured by plasma biomarkers. This integrated approach highlights plasma p-Tau217 as a primary screening tool for amyloid pathology to guide disease-modifying therapies (DMTs), alongside eZIS for tracking follow-up mixed co-pathologies.