Rethinking tau-targeted therapy in Alzheimer's disease: Toward a dual biomarker strategy

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.