Active neurons demand more blood—this coupling is brain's vital delivery service. Amyloid severs this connection, starving active tissue precisely when fuel is needed most.

The Mechanism:

Normal Coupling: Neural activity releases vasodilators (nitric oxide, prostaglandins) acting on endothelial cells, signaling smooth muscle relaxation and capillary dilation.

Amyloid Interception: Aβ binds directly to endothelial receptors (CD36, RAGE) on capillary walls. This triggers endothelin-1 release a potent vasoconstrictor.

Paradoxical Response: Instead of dilating, amyloid-laden capillaries constrict during neural activity. Blood flow decreases precisely when demand increases.

Energy Crisis: Active neurons cannot sustain firing without glucose/oxygen supply. Synaptic transmission fails, plasticity impaired, ATP depletion triggers stress pathways.

Chronic Mismatch: Repeated coupling failures create cumulative energy deficits. Hypoperfusion increases BACE1 via HIF1��, generating more amyloid feed-forward loop.

Early Biomarker: fMRI shows impaired neurovascular coupling in MCI patients before atrophy functional failure precedes structural damage.

Therapeutic Implications:

Endothelin receptor blockers preventing paradoxical constriction

Nitric oxide donors overriding vasoconstrictive signals

RAGE antagonists blocking amyloid-endothelial binding

Vascular protective agents preserving endothelial function

This reframes AD as hemodynamic mismatch brain calls for fuel but vessels strangle supply.