Regional RO948 tau-PET across the AD continuum in relation to plasma biomarkers, cognition and atrophy

Understanding tau pathology progression across the Alzheimers disease (AD) continuum is critical for diagnosis and stratification. This study examined how age of onset and disease stage influence regional tau deposition using [{superscript 1}F]RO948-PET, and its relationship with plasma biomarkers, cognition, and cortical atrophy. In total, 57 participants underwent tau-PET, MRI, blood sampling, and neuropsychological testing: 39 patients with MCI (A{beta}-/A{beta}+) or AD, and 18 cognitively normal controls. The MCI A{beta}+ and AD groups were further divided into early-onset (EOAD, <65y) and late-onset (LOAD, >65y) subgroups. MCI A{beta}+ patients showed early tau accumulation in medial-temporal regions, extending to inferior-temporal cortex. MCI-EOAD exhibited more advanced neocortical tau binding, while MCI-LOAD showed intermediate lateral temporal involvement. In AD, EOAD patients had higher parietal tau burden than LOAD. Plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NFL) were elevated in MCI A{beta}+ and AD. Plasma p-tau217 showed strong correlations with tau-PET in medial and inferior temporal regions, with weaker correlations in neocortical areas. EOAD showed non-linear tau-PET/p-tau217 associations, contrasting with LOADs linear pattern. Tau-PET was negatively correlated with global cognition and executive function, while p-tau217 better reflected early episodic memory decline. Both tau measures correlated with cortical thinning, especially in the entorhinal cortex. These findings highlight [{superscript 1}F]RO948-PETs sensitivity in detecting early tau pathology and superiority in capturing individual differences in tau burden, particularly in advanced stages where plasma biomarkers plateaued. Tau-PET demonstrated superior resolution of disease progression and individual variability, reinforcing its value as a prognostic biomarker and a critical tool for patient stratification in clinical trials. One Sentence Summary[{superscript 1}F]RO948 tau-PET detects early tau pathology and onset-related patterns, outperforming plasma biomarkers in tracking Alzheimers progression.