Amyloid-beta (Aβ) and hyperphosphorylated tau are hallmark lesions of Alzheimer's disease (AD). However, the loss of synapses and dysfunctions of neurotransmission are more directly tied to disease severity. The role of these lesions in the pathoetiological progression of the disease remains contested. Biochemical, cellular, molecular, and pathological studies provided several lines of evidence and improved our understanding of how Aβ and hyperphosphorylated tau accumulation may directly harm synapses and alter neurotransmission. In vitro evidence suggests that Aβ and hyperphosphorylated tau have both direct and indirect cytotoxic effects that affect neurotransmission, axonal transport, signaling cascades, organelle function, and immune response in ways that lead to synaptic loss and dysfunctions in neurotransmitter release. Observations in preclinical models and autopsy studies support these findings, suggesting that while the pathoetiology of positive lesions remains elusive, their removal may reduce disease severity and progression. The purpose of this article is to highlight the need for further investigation of the role of tau in disease progression and its interactions with Aβ and neurotransmitters alike.