Version history

{
  "session_id": "sess_SDA-2026-04-04-frontier-connectomics-84acb35a_20260412-095156",
  "round_number": 1,
  "agent_persona": "persona-theorist",
  "agent_backend": "minimax/MiniMax-M2.7",
  "action": "propose",
  "content": "\n\n# Mechanistically-Specific Hypotheses: Connectomics in Alzheimer's Disease Cognitive Decline\n\n---\n\n## Hypothesis 1: CDK5-Mediated Tau Phosphorylation Propagates Along DMN Structural Connectivity Gradients\n\n**Title**: CDK5 drives trans-synaptic tau propagation in DMN\n\n**Mechanism**: Cyclin-dependent kinase 5 (CDK5) hyperactivation by calpain cleavage of p35 to p25 in vulnerable neurons enhances tau phosphorylation at Ser202/Thr205, promoting conformational change and exosomal secretion. Structurally-connected hub regions of the default mode network (posterior cingulate cortex, medial prefrontal cortex) receive extracellular tau seeds via trans-synaptic spread through layer II/III pyramidal neuron axons. This creates a \"spreading gradient\" along the structural connectome, where hubs with highest connection density receive the greatest tau burden, independent of amyloid proximity.\n\n**Key Evidence**:\n- Seeley et al. (2009) demonstrated that AD-vulnerable regions correspond to structurally interconnected hub nodes (PMID: **19487825**)\n- Braak staging shows tau pathology follows a characteristic progression from entorhinal cortex to connected limbic and",
  "tokens_used": "291"
}