Aβ1-42-derived diffusible ligands (ADDLs) are potent neurotoxins that act on the central nervous system (CNS). These small, nonfibrillar oligomers, which assemble in the absence of fibril formation, are highly toxic to mature neurons at nanomolar concentrations. ADDLs bind to trypsin-sensitive cell surface sites and are neutralized by surface-derived tryptic peptides. They also bind to Fyn, a protein tyrosine kinase elevated in Alzheimer's disease (AD), and its knockout provides neuroprotection. Neurological dysfunction caused by ADDLs occurs before cellular degeneration, and they inhibit hippocampal long-term potentiation (LTP), indicating immediate effects on signal transduction. These findings suggest that ADDLs may contribute to early memory loss and later dementia in AD by disrupting synaptic plasticity and neuronal death through specific signal transduction pathways. ADDLs are found in AD brain tissue and are associated with amyloid plaques. Their neurotoxicity is independent of fibrillar Aβ and is enhanced by factors such as clusterin. ADDLs are soluble, diffusible, and bind to specific cell surface proteins, making them a potential target for therapeutic intervention in AD. The study highlights the importance of understanding ADDLs in the pathogenesis of Alzheimer's disease.Aβ1-42-derived diffusible ligands (ADDLs) are potent neurotoxins that act on the central nervous system (CNS). These small, nonfibrillar oligomers, which assemble in the absence of fibril formation, are highly toxic to mature neurons at nanomolar concentrations. ADDLs bind to trypsin-sensitive cell surface sites and are neutralized by surface-derived tryptic peptides. They also bind to Fyn, a protein tyrosine kinase elevated in Alzheimer's disease (AD), and its knockout provides neuroprotection. Neurological dysfunction caused by ADDLs occurs before cellular degeneration, and they inhibit hippocampal long-term potentiation (LTP), indicating immediate effects on signal transduction. These findings suggest that ADDLs may contribute to early memory loss and later dementia in AD by disrupting synaptic plasticity and neuronal death through specific signal transduction pathways. ADDLs are found in AD brain tissue and are associated with amyloid plaques. Their neurotoxicity is independent of fibrillar Aβ and is enhanced by factors such as clusterin. ADDLs are soluble, diffusible, and bind to specific cell surface proteins, making them a potential target for therapeutic intervention in AD. The study highlights the importance of understanding ADDLs in the pathogenesis of Alzheimer's disease.