Soluble oligomers of the amyloid β-protein (Aβ) impair synaptic plasticity and behavior in Alzheimer's disease (AD). Over the past 25 years, research has shown that the accumulation of Aβ in the brain, particularly in limbic and association cortices, triggers a cascade of biochemical and cellular changes leading to AD. While the reasons for elevated Aβ42 levels in AD patients are unclear, recent studies suggest that increased neuronal release of Aβ during synaptic activity may contribute. Soluble Aβ42 monomers can form oligomers that diffuse into synaptic clefts and disrupt hippocampal long-term potentiation (LTP) and memory in rats. Aβ trimers are more potent than dimers in disrupting LTP. These oligomers also reduce dendritic spine density in hippocampal cultures, an effect that can be prevented by Aβ antibodies or small-molecule modulators. Therapeutic progress has been accompanied by advances in non-invasive imaging of Aβ deposits in humans. A new diagnostic-therapeutic paradigm is emerging to address AD and its precursor, mild cognitive impairment (MCI). Natural secreted Aβ oligomers, unlike synthetic ones, are produced at low nanomolar concentrations and can disrupt synaptic function. Studies show that these oligomers inhibit LTP in the hippocampus and impair complex learned behaviors in rats. They also reduce dendritic spine density in hippocampal cultures, an effect blocked by NMDA receptor antagonists. These findings suggest that Aβ oligomers impair both synaptic function and structure in the hippocampus. Therapeutically, antibodies and small-molecule inhibitors of Aβ aggregation can prevent oligomer-mediated spine loss. The study highlights the role of NMDA receptor activity in Aβ oligomer-induced spine loss and suggests that chronic activation of these pathways contributes to AD pathogenesis. The research underscores the importance of targeting Aβ oligomers in the development of therapies for AD.Soluble oligomers of the amyloid β-protein (Aβ) impair synaptic plasticity and behavior in Alzheimer's disease (AD). Over the past 25 years, research has shown that the accumulation of Aβ in the brain, particularly in limbic and association cortices, triggers a cascade of biochemical and cellular changes leading to AD. While the reasons for elevated Aβ42 levels in AD patients are unclear, recent studies suggest that increased neuronal release of Aβ during synaptic activity may contribute. Soluble Aβ42 monomers can form oligomers that diffuse into synaptic clefts and disrupt hippocampal long-term potentiation (LTP) and memory in rats. Aβ trimers are more potent than dimers in disrupting LTP. These oligomers also reduce dendritic spine density in hippocampal cultures, an effect that can be prevented by Aβ antibodies or small-molecule modulators. Therapeutic progress has been accompanied by advances in non-invasive imaging of Aβ deposits in humans. A new diagnostic-therapeutic paradigm is emerging to address AD and its precursor, mild cognitive impairment (MCI). Natural secreted Aβ oligomers, unlike synthetic ones, are produced at low nanomolar concentrations and can disrupt synaptic function. Studies show that these oligomers inhibit LTP in the hippocampus and impair complex learned behaviors in rats. They also reduce dendritic spine density in hippocampal cultures, an effect blocked by NMDA receptor antagonists. These findings suggest that Aβ oligomers impair both synaptic function and structure in the hippocampus. Therapeutically, antibodies and small-molecule inhibitors of Aβ aggregation can prevent oligomer-mediated spine loss. The study highlights the role of NMDA receptor activity in Aβ oligomer-induced spine loss and suggests that chronic activation of these pathways contributes to AD pathogenesis. The research underscores the importance of targeting Aβ oligomers in the development of therapies for AD.