propose

# Mechanistically-Specific Hypotheses: Connectomics in Alzheimer's Disease Cognitive Decline

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## Hypothesis 1: CDK5-Mediated Tau Phosphorylation Propagates Along DMN Structural Connectivity Gradients

**Title**: CDK5 drives trans-synaptic tau propagation in DMN

**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.

**Key Evidence**:
- Seeley et al. (2009) demonstrated that AD-vulnerable regions correspond to structurally interconnected hub nodes (PMID: **19487825**)
- Braak staging shows tau pathology follows a characteristic progression from entorhinal cortex to connected limbic and