Shi_2026_ChemMedChem_21_e70384

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving interconnected pathological pathways, including cholinergic dysfunction, Abeta deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and dysregulation of metal ion homeostasis. Recently, the "one drug, one target" paradigm has faced certain clinical limitations, driving a paradigm shift toward multi-target therapeutic strategies. In this context, tricyclic scaffolds, characterized by rigid fused-ring skeletons, excellent structural tunability, and favorable neuropharmacological properties, have emerged as promising scaffolds for developing multi-target AD therapeutics. These molecules can interact with multiple AD-related targets through stable Pi-Pi stacking and hydrophobic interactions. Some tricyclic scaffolds, such as tetrahydrocarbolines, share structural similarity with endogenous neurotransmitters, suggesting potential involvement in modulating cognitive and mood-related pathways, along with favorable BBB permeability and neuro-compatibility. Accordingly, this review begins by outlining the distinct pathological mechanisms underlying AD, followed by a summary of recent progress on tricyclic compounds, encompassing both single-target and multi-target-directed molecules, with an emphasis on structure-activity relationships and mechanisms of action, aiming to offer new insights and strategies for combating this devastating disease.