The most prevalent form of dementia in the elderly is Alzheimer’s disease. A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42 (Aβ42), a small hydrophobic peptide. Unfortunately, attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease. It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach. The accumulation of Aβ42 seems to affect various aspects of physiological cell functions. In this review, we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction, with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release. We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer’s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease. Although the precise mechanisms that trigger synaptic dysfunction are still under investigation, the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.