Therapeutic Potential of Somatostatin and Its Analogues in Alzheimer's Disease: From Molecular Mechanisms to Preclinical Studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Currently approved agents, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only modest symptomatic benefit without modifying disease progression. Increasing evidence highlights the somatostatin (SST) system and its analogues (SSAs) as potential multitarget therapies. Somatostatin receptors (SSTR1-5) are widely expressed in cognition-related brain regions and participate in amyloid-β metabolism, tau phosphorylation, neuroinflammation, and synaptic plasticity. Preclinical studies suggest that SSAs enhance amyloid clearance via neprilysin activation, attenuate tau pathology through PI3K/Akt signaling, regulate APOE4 expression, and modulate microglial function, thereby protecting synaptic integrity. Compared with current monotherapies, SSAs may provide broader therapeutic benefits, particularly if applied in prodromal or early stages of AD. Advances in delivery strategies, including peptide modification, nanocarrier-based transport, and physically assisted blood-brain barrier (BBB) penetration, further improve translational potential. However, challenges such as poor BBB permeability, incomplete mechanistic understanding, and limited clinical data remain. Integration of systems biology, biomarker-driven precision medicine, and novel delivery technologies may facilitate the development of SSA-based interventions as complementary strategies for AD management.