Concurrent longitudinal changes in plasma p-tau217, tau PET, and cognition in preclinical Alzheimer’s disease
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Background
Plasma p-tau217 and tau PET are biomarkers reflecting partly different aspects of Alzheimer’s disease pathology. Plasma p-tau217 may become abnormal earlier in the disease process, potentially capturing the initial alterations of tau metabolism, whereas tau PET provides spatially detailed information about aggregated tau that could more closely reflect ongoing changes impacting cognitive outcomes. How these two markers evolve over time, whether they diverge in their relationship to cognition, and their potential to assess disease modification in treatment trials are unknown.
Methods
Analyses included data from 1707 participants (1169 Aβ+, 538 Aβ–) enrolled in the A4 and LEARN studies, with a subset of 443 (388 Aβ+, 55 Aβ–) receiving tau PET scans. All participants were aged 65–85, cognitively-unimpaired at baseline, and followed for up to eight years. Longitudinal changes in tau PET signal ( 18 F-flortaucipir) across 28 bilateral regions, plasma p-tau217, and cognition (Preclinical Alzheimer’s Cognitive Composite [PACC]) were assessed using mixed-effects regression. The correlation between biomarker changes and cognitive decline was estimated using Bayesian joint longitudinal mixed-models.
Results
All cognitive outcomes showed strong nonlinear trajectories associated with Aβ-positivity. In Aβ+ participants, the largest effect sizes of longitudinal tau PET accumulation at 36-months were in the inferior temporal gyrus (ITG), fusiform (FUSI), and entorhinal cortex (ERC). Pronounced acceleration over the course of follow-up was observed in the ITG and the middle temporal gyrus (MTG) and the inferior parietal lobule (IPL). Baseline associations with longitudinal change in the PACC were strongest in ERC: correlation (ρ) = −0.55 (−0.63, −0.45), and plasma p-tau217: ρ =−0.47 (−0.56, −0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent changes in cognition. Correlations with change in the PACC ranged from −0.65 to −0.61 in the precuneus (PRE), superior parietal lobule (SPL), caudal middle frontal (CMF) and superior frontal gyri. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ 2 = 21.7, p < 0.001) and was not associated with concurrent cognitive change, ρ = −0.03 (−0.23 to 0.16).
Conclusion
These findings highlight the value of tau PET for both prognostic and real time tracking of disease progression. While plasma p-tau217 may serve as an efficient and scalable biomarker with high prognostic value, region-specific tau PET signals track with concurrent cognitive decline. These results support the inclusion of plasma p-tau217 to guide participant selection and imaging-based tau measures to enhance detection of disease-modifying effects and to refine therapeutic targets in future AD trials.
