This challenge targets the hypothesis: **VHH-Fc Fusion Constructs with Separate BBB-Targeting Moiety** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The VHH-Fc fusion construct leveraging separate blood-brain barrier (BBB) targeting moieties represents an innovative approach to neurodegeneration therapeutics that exploits the unique properties of heavy-chain-only antibodies (VHHs) while addressing the critical challenge of brain drug delivery. The molecular foundation of this strategy centers on the FCGRT gene encoding the neonatal Fc receptor (FcRn), which forms a functional heterodimeric complex with **Falsifiable Predictions:** 1. Pharmacological modulation of FCGRT (FcRn); FCGRT-β2M complex 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.