FIGURE 1.

Pathway to noradrenergic dysregulation in Alzheimer's Disease: 1) Due to a combination of genetic and environmental factors, amyloid plaques and tauopathies occur in the Locus Coeruleus (LC) decades before symptom onset. 2) LC neuron count decreases and tauopathy spreads along anterior pathway to the forebrain and cortex during an asymptomatic period in middle‐age. Remaining noradrenergic (NA) neurons exhibit compensatory alterations. 3) NA system integrity is lost due to maladaptive LC changes. α and β AR expression alters across various brain regions, further disrupting connectivity. 4) Tauopathy spreads to the NBM. Hyperactive NA neurons may further inhibit the remaining cholinergic neurons. Widespread dysfunction occurs across multiple systems