propose

# Mechanistic Hypotheses: ApoE-Dependent CAA Formation

## Hypothesis 1: ApoE-Aβ Seeding Efficiency Driven by N-terminal Amphipathic Helix Flexibility

**Mechanism**: ApoE facilitates Aβ deposition through isoform-dependent structural remodeling of the N-terminal amphipathic helix (residues 1-183 in human apoE), where apoE4's increased helix stability—due to domain interaction with the C-terminal domain—reduces conformational flexibility required for Aβ recognition. This creates a paradox: apoE4's superior Aβ binding actually promotes nucleation rather than clearance by stabilizing oligomeric intermediates that preferentially deposit on vascular basement membranes.

**Key Evidence**: Castellano et al. (2011) demonstrated that apoE isoforms