Baseline and long‐term longitudinal atrophy patterns of cognitively unimpaired individuals with elevated plasma ptau‐217

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BACKGROUND: Plasma p-tau217 is an emerging biomarker for Alzheimer's disease (AD) and has been shown to be a strong predictor of cognitive decline even in cognitively unimpaired (CU) individuals. However, little is known about the association of elevated plasma p-tau217 with long-term neurodegenerative trajectories. This study aims to characterize cross-sectional and longitudinal patterns of gray matter atrophy in CU individuals with elevated plasma p-tau217 levels. METHOD: 1030 CU older individuals (74.9±3.9 yrs; 65.1% female) from the Vallecas Project cohort at the CIEN Foundation (Madrid) were included in this study. All participants underwent blood sampling, clinical and neuropsychological evaluations, and 3T-MRI scanning at baseline, and 863 individuals had annual longitudinal follow-up assessments for up to ten years (average follow-up: 5.4±2.6 yrs; for a total of 4646 MRI acquisitions). Baseline plasma p-tau217 levels were measured using the LUMIPULSE platform, and individuals were classified as having elevated (p-tau217+) or normal (p-tau217-) p-tau217 levels based on a pre-established threshold of 0.247-pg/mL. T1 MRI images were processed in CAT12/SPM12 to obtain segmented gray matter maps, which were analyzed using both ROI-based and voxel-wise approaches. Cross-sectional analyses employed ANCOVA models and longitudinal analyses employed linear mixed effects models. Finally, a mediation analysis was performed to determine whether plasma p-tau217 affects cognitive decline through its impact on longitudinal atrophy. RESULT: 173 participants (16.8%) were classified as p-tau217+. At baseline, these individuals showed significant atrophy of the medial temporal lobe (MTL) compared to p-tau217-, particularly in the hippocampus (Fig-1). Longitudinally, these MTL regions also showed significantly faster atrophy (p <0.001), which partially mediated the effect of plasma p-tau217 on cognitive decline (mediated proportion: 19.4%, p <0.001) (Fig-2). However, voxel-wise longitudinal analyses also revealed a more extensive pattern of accelerated atrophy that extended beyond the MTL, additionally affecting lateral temporal areas, the insula, and the anterior and posterior cingulate cortex (Fig-3). CONCLUSION: This large-scale longitudinal imaging study demonstrates that elevated plasma p-tau217 levels can identify cognitively unimpaired individuals who are on a neurodegenerative trajectory towards AD. This emphasizes the diagnostic value of plasma p-tau217 for early intervention and monitoring of AD progression.

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