Tau pathology is more closely associated with cognitive deterioration than amyloid burden in symptomatic Alzheimer's disease (AD), yet tau-targeted trials have often interpreted decreases in soluble phosphorylated tau (p-tau) as evidence of therapeutic success. Emerging data argue for a more biology-informed framework. P-tau262 and p-tau356 identify sites within soluble pre-tangle tau assemblies, and cerebrospinal (CSF) p-tau262 may decline as neurofibrillary pathology advances. Conversely, marked p-tau217 lowering with posdinemab was not accompanied by clinical benefit. The amyloid field offers a useful but incomplete analogy. Amyloid plaques are extracellular whereas tau misfolding and fibrillization occur predominantly intracellularly, so equivalent relationships among imaging, fluid biomarkers, and clinical outcomes should not be assumed. A recent preprint describing a functional plasma assay of pathologically active tau reported high discrimination of tau positron emission tomography (PET) positivity, particularly at early tau PET stages, illustrating how seeding-related activity may add information beyond p-tau concentration. We propose a dual-domain framework in which tau-targeted therapies are evaluated using complementary measures of aggregated tau burden and biologically defined soluble tau states. P-tau262 is one candidate within the soluble domain, but treatment-induced increases should be considered favorable only when they accompany aggregate reduction and evidence of a less pathogenic soluble state. This framework applies across antibodies, antisense oligonucleotides, and other biologic tau-directed strategies. Future trials should test joint biomarker-clinical response functions rather than importing thresholds from anti-amyloid therapy, and should prespecify adequately powered analyses of sex, population background, disease stage, and other potential modifiers.
C. Teunissen, L. Pini, B. Imbimbo· Alzheimer's & Dementia· 0 citations
Tau positron emission tomography (PET) has become a central imaging modality for in vivo detection and quantification of tau pathology across the Alzheimer's disease (AD) clinical and biological continuum. [18F]-Florzolotau is a second-generation tau PET tracer developed to improve target-to-background contrast and mitigate off-target binding relative to first-generation ligands, thereby improving interpretability for translational research and clinical use. In this narrative review, we provide a critical appraisal of the available literature on [18F]-Florzolotau PET imaging in AD, with emphasis on diagnostic and differential-diagnostic performance, the spatiotemporal topography of tau deposition in relation to Braak staging and disease progression, and the clinical significance of tracer uptake with respect to cognitive measures, disease severity, and prognosis. Eligible studies were clinical investigations published between 2020 and 2025 that applied [18F]-Florzolotau PET in cohorts spanning cognitively unimpaired individuals through symptomatic AD stages. Across reports, [18F]-Florzolotau PET differentiated AD dementia from cognitively unimpaired comparators with high accuracy, with sensitivities ≥ 90% and specificities of 87–96%. Regional uptake patterns were broadly consistent with Braak-like propagation, progressing from medial temporal regions toward associative neocortex in parallel with increasing clinical severity. Quantitative tracer uptake also correlated with global cognition and key domains, including episodic memory and executive function. We conclude that [18F]-Florzolotau PET provides a robust in vivo measure of AD tau burden, motivating further evaluation for diagnostic and prognostic applications. Larger multicenter studies with harmonized acquisition/quantification and head-to-head comparisons versus other second-generation tracers remain priorities.
Simone Lista, P. Minoretti, Enzo Emanuele et al.· Journal of Alzheimer's Disea...· 0 citations
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