The Central Premise: Pericytes are the brain's capillary gatekeepers they regulate blood flow and maintain barrier integrity. Amyloid kills them silently, starving tissue years before symptoms emerge.

The Mechanism:

Amyloid Toxicity: Soluble Aβ oligomers bind to pericytes via RAGE receptors, triggering oxidative stress and apoptosis. Pericytes are particularly vulnerable they lack antioxidant defenses.

Capillary Constriction: Pericytes control capillary diameter. When they die, capillaries remain constricted or collapse. Blood flow drops 30-50% in affected regions.

Chronic Hypoperfusion: Reduced capillary flow creates chronic energy crisis neurons receive less oxygen and glucose. ATP depletion impairs synaptic function, protein synthesis, and clearance.

BBB Breakdown: Pericyte loss compromises tight junctions. Blood-derived toxins (fibrinogen, thrombin) enter parenchyma, activating microglia and damaging neurons.

Feed-Forward Loop: Hypoperfusion increases BACE1 expression via HIF1��, generating more amyloid. More amyloid kills more pericytes.

Therapeutic Implications:

PDGFR�� agonists promoting pericyte survival

Vasodilators overcoming capillary constriction

RAGE antagonists blocking amyloid-pericyte binding

Pericyte transplantation restoring coverage

This reframes AD as vascular disease capillary failure driving neuronal starvation.