Somatostatinergic and dopaminergic systems in Alzheimer’s disease: Mechanistic insights and therapeutic opportunities beyond plaques and tangles

Alzheimer's disease therapeutic development has largely focused on amyloid-β and tau pathologies, with limited clinical success. This review extends beyond the canonical amyloid/tau paradigm by examining the roles of somatostatin and dopamine neuromodulatory systems, which undergo early degeneration in Alzheimer's disease and contribute mechanistically to disease progression. Somatostatin deficiency impairs amyloid-β clearance by downregulating neprilysin activity and disrupts inhibitory network homeostasis. Somatostatin binds amyloid-β oligomers and attenuates tau hyperphosphorylation via kinase modulation and cytoskeletal stabilization. Dopaminergic deficits, particularly in ventral tegmental and cortical projections, disrupt synaptic plasticity, memory encoding, network oscillations, and neurogenesis. Dopamine receptor activation promotes amyloid-β clearance, enhances autophagy, and modulates tau phosphorylation. The intersection of somatostatin and dopamine pathways through receptor heteromerization and intersecting intracellular cascades delineates a promising therapeutic axis. Preclinical evidence demonstrates that somatostatin and dopamine receptor agonists mitigate amyloid and tau pathologies and preserve cognitive function, attesting the need for integrative therapeutic strategies targeting neural network dysfunction in Alzheimer's disease.