propose

# Mechanistically-Specific Hypotheses: Peripheral Immune Contributions to Alzheimer Disease Pathology

## Hypothesis 1: CCR2+ Monocyte Recruitment Imposes a Functional Phagocytosis-to-Proteolysis Phenotype Switch in the Perivascular Space

**Mechanism:**
Peripheral classical monocytes (Ly6C^high in mice, CD14++CD16− in humans) are recruited to perivascular spaces and the leptomeningeal vasculature via neuronally-secreted CCL2 binding to CCR2. Once recruited, these cells adopt a "proteolytic" phenotype characterized by upregulated MMP-2 and MMP-9 expression, which degrades components of the neurovascular unit (especially pericyte basal lamina and tight junction proteins) while simultaneously impairing Aβ clearance by internalized receptor downregulation (e.g., CD36, TREM2). This creates a self-reinforcing cycle: recruited monocytes