This challenge targets the hypothesis: **Tau dysfunction destabilizes labile pool** **Hypothesis Summary:** Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains Prediction: Tau-targeted interventions will selectively impair transport of organelles requiring labile microtubules (mitochondria, endosomes) while sparing lysosome transport **Falsifiable Predictions:** 1. Pharmacological modulation of MAPT will alter neurodegeneration markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $125,000 USD (composite score 0.750) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.