Question
Does APOE4-driven impairment of oligodendrocyte cholesterol efflux via reduced LXRβ signaling cause myelin instability, and can selective LXRβ agonism restore myelin maintenance in APOE4-carrier AD patients?
Falsifiable prediction from high-scoring hypothesis (score=0.721, gene=NR1H2 (LXRβ)). Hypothesis: Does APOE4-driven impairment of oligodendrocyte cholesterol efflux via reduced LXRβ signaling cause myelin instability, and can selective LXRβ agonism restore myelin maintenance in APOE4-carrier AD patients? Success criteria: 1. APOE4 oligodendrocytes show >40% reduction in MBP+ processes vs APOE3 in primary culture; LXRβ agonist restores to >80% of APOE3 levels. 2. DTI-MRI (Fractional Anisotropy) improves by >15% in corpus callosum of LXRβ-treated APOE4-KI mice. 3. Nodes of Ranvier length and periodicity normalize (>90% of WT) with LXRβ agonist treatment. 4. Working memory (Y-maze alternation) improves by >30% in LXRβ-treated APOE4 vs vehicle mice.