A decade of research has shown that the accumulation of amyloid β-protein (Aβ) plays a central role in Alzheimer's disease (AD). Initially, it was believed that Aβ had to form extracellular amyloid fibrils to be toxic, but recent evidence suggests that pre-fibrillar, diffusible assemblies of Aβ are also harmful. Aβ is derived from the β-amyloid precursor protein (APP) through cleavage by β- and γ-secretases. Three main forms of Aβ are produced, with Aβ42 being more prone to oligomerization and fibril formation. Genetic, animal, and biochemical studies support Aβ's role in AD, including the association of Aβ with Down syndrome and the effects of mutations in APP and presenilin genes. Evidence for Aβ's role in AD includes the presence of Aβ in Down syndrome, the toxicity of synthetic Aβ peptides, inherited mutations in APP, and the influence of ApoE alleles on Aβ levels. Studies in mice and humans show that soluble Aβ oligomers, rather than fibrils, are the primary mediators of synaptic dysfunction and neuronal injury. Pre-fibrillar Aβ assemblies are present in human brains and APP transgenic mice, and their levels correlate with synaptic loss and cognitive impairment. Cell-derived Aβ oligomers are potent synaptotoxins, causing synaptic loss and impairing memory. Synthetic Aβ oligomers, such as ADDLs and PFs, are toxic and can disrupt neuronal function. These assemblies are distinct from fibrils and have unique biological activities. Therapeutic strategies targeting Aβ oligomers include reducing their production, enhancing their degradation, and using antibodies or small molecules to neutralize them. Future research aims to better characterize Aβ assemblies in the brain and develop effective therapies that prevent or reverse AD progression. Understanding the mechanisms of Aβ toxicity and the role of different oligomeric forms is crucial for developing targeted treatments.A decade of research has shown that the accumulation of amyloid β-protein (Aβ) plays a central role in Alzheimer's disease (AD). Initially, it was believed that Aβ had to form extracellular amyloid fibrils to be toxic, but recent evidence suggests that pre-fibrillar, diffusible assemblies of Aβ are also harmful. Aβ is derived from the β-amyloid precursor protein (APP) through cleavage by β- and γ-secretases. Three main forms of Aβ are produced, with Aβ42 being more prone to oligomerization and fibril formation. Genetic, animal, and biochemical studies support Aβ's role in AD, including the association of Aβ with Down syndrome and the effects of mutations in APP and presenilin genes. Evidence for Aβ's role in AD includes the presence of Aβ in Down syndrome, the toxicity of synthetic Aβ peptides, inherited mutations in APP, and the influence of ApoE alleles on Aβ levels. Studies in mice and humans show that soluble Aβ oligomers, rather than fibrils, are the primary mediators of synaptic dysfunction and neuronal injury. Pre-fibrillar Aβ assemblies are present in human brains and APP transgenic mice, and their levels correlate with synaptic loss and cognitive impairment. Cell-derived Aβ oligomers are potent synaptotoxins, causing synaptic loss and impairing memory. Synthetic Aβ oligomers, such as ADDLs and PFs, are toxic and can disrupt neuronal function. These assemblies are distinct from fibrils and have unique biological activities. Therapeutic strategies targeting Aβ oligomers include reducing their production, enhancing their degradation, and using antibodies or small molecules to neutralize them. Future research aims to better characterize Aβ assemblies in the brain and develop effective therapies that prevent or reverse AD progression. Understanding the mechanisms of Aβ toxicity and the role of different oligomeric forms is crucial for developing targeted treatments.