Neurotoxic β-amyloid oligomers (AβOs) cause mitochondrial dysfunction, triggering PANoptosis in neurons. Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing prevalence as the global population ages. While β-amyloid (Aβ) deposition is a key factor in AD, the clinical efficacy of anti-Aβ therapies is limited, suggesting AβO may be more harmful than plaques. AβO, a soluble oligomeric form of Aβ, is believed to be the primary cause of neurotoxicity in AD, leading to neuronal death. Mitochondrial dysfunction, a critical factor in neuronal survival, is disrupted by AβO, leading to the release of toxic contents and triggering PANoptosis, a novel form of programmed cell death involving pyroptosis, apoptosis, and necroptosis. Mitochondrial dysfunction in neurons is closely linked to AβO, and understanding this mechanism is crucial for developing targeted therapies. AβO enters neurons through endocytosis and binds to membrane receptors, causing membrane damage and intracellular Ca²⁺ influx. AβO also spreads between neurons, contributing to neurotoxicity. AβO disrupts mitochondrial dynamics, leading to mitochondrial fragmentation, impaired ATP production, and increased ROS. AβO also affects mitochondrial membrane permeability and cristae structure, leading to mitochondrial dysfunction and neuronal death. AβO impairs mitochondrial respiratory chain function and energy metabolism, reducing ATP production and impairing glucose uptake. These findings highlight the critical role of mitochondrial dysfunction in AD pathogenesis and suggest that targeting mitochondrial function could be a promising therapeutic strategy for AD.Neurotoxic β-amyloid oligomers (AβOs) cause mitochondrial dysfunction, triggering PANoptosis in neurons. Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing prevalence as the global population ages. While β-amyloid (Aβ) deposition is a key factor in AD, the clinical efficacy of anti-Aβ therapies is limited, suggesting AβO may be more harmful than plaques. AβO, a soluble oligomeric form of Aβ, is believed to be the primary cause of neurotoxicity in AD, leading to neuronal death. Mitochondrial dysfunction, a critical factor in neuronal survival, is disrupted by AβO, leading to the release of toxic contents and triggering PANoptosis, a novel form of programmed cell death involving pyroptosis, apoptosis, and necroptosis. Mitochondrial dysfunction in neurons is closely linked to AβO, and understanding this mechanism is crucial for developing targeted therapies. AβO enters neurons through endocytosis and binds to membrane receptors, causing membrane damage and intracellular Ca²⁺ influx. AβO also spreads between neurons, contributing to neurotoxicity. AβO disrupts mitochondrial dynamics, leading to mitochondrial fragmentation, impaired ATP production, and increased ROS. AβO also affects mitochondrial membrane permeability and cristae structure, leading to mitochondrial dysfunction and neuronal death. AβO impairs mitochondrial respiratory chain function and energy metabolism, reducing ATP production and impairing glucose uptake. These findings highlight the critical role of mitochondrial dysfunction in AD pathogenesis and suggest that targeting mitochondrial function could be a promising therapeutic strategy for AD.