Individuals at distinct stages of Alzheimer’s disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes at the synaptic level are observed in brain areas affected early in AD, and if they are emergent in MCI, is a matter of current research. Equally important, whether global synaptic E/I imbalances correlate with the severity of cognitive impairment in the continuum of AD is also the focus of much research. In this seminar, it will be discussed recent results indicating that pro-excitatory shifts of the excitatory to inhibitory (E/I) postsynaptic imbalance correlates positively with toxic proteins in synapses and the global degree of pathology; and impinges negatively on cognitive performance scores. These relationships are observed across different levels of molecular complexity, from the transcriptome to the synaptic-proteome, providing a better picture of brain activity changes in the AD brain that are associated with the AD symptoms. Finally, it will be discussed how alterations in the E/I ratio are currently being measured in other brain mental health disorders to explore the convergence and divergence of disease cognitive phenotypes.