Hypothesis Comparison

graph TD
    A["APOE4 Genetic Variant"]
    B["Structural Domain Interaction"]
    C["Impaired Lipid Binding Affinity"]
    D["Reduced HDL-like Particle Formation"]
    E["Compromised Neuronal Lipid Transport"]
    F["Membrane Cholesterol Dysregulation"]
    G["Synaptic Membrane Instability"]
    H["Microglial Activation"]
    I["Neuroinflammatory Response"]
    J["Amyloid-beta Accumulation"]
    K["Tau Hyperphosphorylation"]
    L["APOE4-Selective Lipid Nanoemulsion"]
    M["Neuronal Cell Death"]
    N["Cognitive Decline"]
    O["Therapeutic Lipid Replacement"]

    A -->|"Arg112/Arg158 substitution"| B
    B -->|"altered protein conformation"| C
    C -->|"decreased cholesterol binding"| D
    D -->|"inefficient particle assembly"| E
    E -->|"disrupted homeostasis"| F
    F -->|"membrane dysfunction"| G
    G -->|"synaptic failure"| M
    E -->|"lipid stress"| H
    H -->|"pro-inflammatory cytokines"| I
    I -->|"enhanced amyloidogenesis"| J
    F -->|"cellular stress response"| K
    J -->|"synaptic toxicity"| M
    K -->|"neurofibrillary tangles"| M
    M -->|"neuronal loss"| N
    L -->|"targeted lipid delivery"| O
    O -->|"membrane stabilization"| F

    classDef genetics fill:#ce93d8
    classDef mechanism fill:#4fc3f7
    classDef pathology fill:#ef5350
    classDef therapy fill:#81c784
    classDef outcome fill:#ffd54f

    class A genetics
    class B,C,D,E,F,G,H,I,O mechanism
    class J,K,M pathology
    class L therapy
    class N outcome

graph TD
    subgraph Disease["Neurodegeneration Triggers"]
        A["Amyloid beta accumulation"] -->|"activates"| B["Microglial activation"]
        C["Tau pathology"] -->|"triggers"| B
        D["Lipid dysregulation"] -->|"impairs"| E["APOE function"]
    end
    
    subgraph Molecular["APOE-TREM2 Molecular Interaction"]
        E["APOE lipoprotein particles"] -->|"binds to"| F["TREM2 extracellular domain"]
        F -->|"signals through"| G["TYROBP/DAP12 adaptor"]
        G -->|"activates"| H["SYK kinase phosphorylation"]
        H -->|"triggers"| I["PI3K-AKT-mTOR cascade"]
    end
    
    subgraph Response["Microglial Response States"]
        B -->|"without TREM2 signaling"| J["Inflammatory M1 activation"]
        I -->|"promotes"| K["Protective M2 activation"]
        J -->|"produces"| L["Pro-inflammatory cytokines"]
        K -->|"enhances"| M["Phagocytic clearance"]
        K -->|"increases"| N["Anti-inflammatory mediators"]
    end
    
    subgraph Intervention["Therapeutic Enhancement"]
        O["Small molecule enhancers"] -->|"stabilizes"| F
        P["APOE mimetic peptides"] -->|"augments"| E
        O -->|"increases"| I
    end
    
    subgraph Outcomes["Clinical Outcomes"]
        L -->|"accelerates"| Q["Neuronal death"]
        M -->|"reduces"| R["Amyloid burden"]
        N -->|"protects"| S["Synaptic function"]
        R -->|"improves"| T["Cognitive preservation"]
        S -->|"maintains"| T
    end
    
    style A fill:#ef5350,stroke:#333,color:#000
    style C fill:#ef5350,stroke:#333,color:#000
    style J fill:#ef5350,stroke:#333,color:#000
    style L fill:#ef5350,stroke:#333,color:#000
    style Q fill:#ef5350,stroke:#333,color:#000
    style O fill:#81c784,stroke:#333,color:#000
    style P fill:#81c784,stroke:#333,color:#000
    style F fill:#ce93d8,stroke:#333,color:#000
    style G fill:#4fc3f7,stroke:#333,color:#000
    style H fill:#4fc3f7,stroke:#333,color:#000
    style I fill:#4fc3f7,stroke:#333,color:#000
    style T fill:#ffd54f,stroke:#333,color:#000