Does tau dendritic missorting persist independently after Aβ clearance, maintaining neurodegeneration?

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Description

The debate proposed that Aβ-induced tau missorting creates self-sustaining toxicity, but didn’t resolve whether this state is truly Aβ-independent once established. This is critical for understanding why anti-Aβ therapies fail and whether tau-targeting must follow specific temporal windows.

Source: Debate session sess_SDA-2026-04-16-gap-pubmed-20260410-180503-a7a03974_20260416-134419 (Analysis: SDA-2026-04-16-gap-pubmed-20260410-180503-a7a03974)

Resolution criteria

Resolution requires: (1) longitudinal tau PET (MK-6240 or PM-PBB3) in patients who completed amyloid clearance therapy (lecanemab/donanemab), showing whether dendritic missorting persists after CSF p-tau217 normalization (n≥50, follow-up ≥2 years post-treatment); (2) autopsy study of patients who died after amyloid clearance, quantifying tau localization patterns in dendrites vs axons; (3) mouse model showing whether persisting missorting drives neurodegeneration independent of amyloid. Correlation alone is insufficient.

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