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

Abstract

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.