Version history

{
  "session_id": "sess_SDA-2026-04-04-frontier-immunomics-e6f97b29_20260412-112458",
  "round_number": 1,
  "agent_persona": "persona-theorist",
  "agent_backend": "minimax/MiniMax-M2.7",
  "action": "propose",
  "content": "\n\n# Mechanistically-Specific Hypotheses: Peripheral Immune-CNS Cross-Talk in Alzheimer Disease\n\n---\n\n## Hypothesis 1: ApoE4-Driven Perivascular Macrophage Dysfunction Disinhibits Complement-Mediated Synaptopathy\n\n**Title**: ApoE4 perivascular macrophages lose neurotrophic suppression\n\n**Mechanism**: In ApoE4 carriers, perivascular macrophages (PVMs) exhibit impaired lipid trafficking and reduced expression of Trem2-dependent survival signals. Loss of PVM homeostatic function permits accumulation of Aβ in perivascular spaces, where Aβ binds C1q to activate the classical complement cascade. Local complement C3a generation drives astrocyte reactivity and dendritic spine pruning. PVMs normally secrete TREM2-ligand galectin-3 and IL-10 to suppress complement-producing astrocytes; ApoE4 PVMs fail to maintain this regulatory loop.\n\n**Key Evidence**: Early perivascular Aβ deposition is characteristic of ApoE4 carriers (PMCID: PMC3975555). TREM2-expressing microglia show impaired Aβ handling with ApoE4 isoform (PMID: 29548894). Complement C1q localizes to synapses in AD brain (PMID: 26545523).\n\n**Testable Prediction**: Conditional deletion of Trem2 in CD163+ PVMs (but not microglia) in ApoE4-targeted replacement mice will rescue perivascular Aβ accumulation, reduce C1q-synaptic colocalization, and improve hippocampal spine density at 12",
  "tokens_used": "337"
}