Alzheimer's disease (AD) is the most common form of dementia. It is characterized by pathological hallmarks such as extracellular deposits of amyloid plaques as well as intracellular neurofibrillary tangles and a progressive loss of neurons. Additional early pathological features of AD also include a decline in synapse number, axonal dystrophies, mitochondrial hypometabolism and increased oxidative stress. It is assumed that the aggregates of amyloid-β and tau are not the major pathogenic players in AD, but that nonaggregated oligomeric forms of amyloid-β and specific phosphorylated forms of tau cause neurodegeneration. It is tempting to speculate that oligomeric amyloid-β and phosphorylated tau might trigger mitochondrial dysfunction associated with oxidative stress as well as dysfunctions of axonal transport, leading to the loss of spines and neurodegeneration. Here, we summarize the actual data supporting this hypothesis and provide a model how these different mechanisms might be intertwined with each other.

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