Version history

{
  "description": "The debate identified elevated CSF SV2A in AD but could not resolve whether glycosylation defects drive hyperexcitability or are downstream consequences. This causal direction determines whether SV2A glycosylation is a therapeutic target or biomarker.\n\nSource: Debate session sess_SDA-2026-04-16-gap-debate-20260411-065018-92a34465_20260416-134725 (Analysis: SDA-2026-04-16-gap-debate-20260411-065018-92a34465)",
  "domain": "neurodegeneration",
  "status": "open",
  "priority_score": 0.85,
  "importance_score": 0.82,
  "tractability_score": 0.75,
  "novelty_score": 0.8,
  "composite_score": 0.6936,
  "estimated_effort": "high",
  "source": "debate:sess_SDA-2026-04-16-gap-debate-20260411-065018-92a34465_20260416-134725",
  "resolution_criteria": "Resolved when an evidence artifact establishes causal direction between SV2A hypoglycosylation and hippocampal hyperexcitability in AD, with one of: (1) temporal perturbation studies in 5xFAD or APP/PS1 mice (models of AD-related hyperexcitability) using SV2A modulators (levetiracetam at 6-50 mg/kg) at different disease stages (pre-symptomatic vs symptomatic), measuring EEG biomarkers (sharp wave ripples, interictal spikes) and SV2A glycosylation status (PNGase F sensitivity assay), establishing whether SV2A glycosylation changes precede or follow hyperexcitability onset; (2) SV2A glycoforms analysis (mass spectrometry or lectin blotting) in human AD hippocampus versus age-matched controls, correlating specific glycoform abundance with synaptic vesicle docking parameters (electron microscopy) and excitability biomarkers (EEG or intracranial EEG from same patients); (3) CRISPR editing of SV2A glycosylation sites (N180Q, N274Q) in neurons or mouse hippocampus, demonstrating that specific glycan loss phenocopies hyperexcitability (>=40% increase in spontaneous firing rate) and that glycan restoration rescues it.",
  "market_price": 0.5
}