Despite a great deal of research into Alzheimer's disease (AD) over the last 20 years, an effective treatment to halt or slow its progression has yet to be developed. With many aspects of the disease progression still to be elucidated, focus has shifted from reducing levels of amyloid β (Aβ) in the brains of AD patients towards tau, another pathology, which initiates much earlier in deeper brainstem networks and is thought to propagate via cell-to-cell processes prior to the onset of amyloid pathology and cognitive impairments. In-vitro, ex-vivo molecular biology/biochemistry read-outs, and various transgenic animal models have been developed, yet clinical failures have highlighted a clear disconnect and inadequate use of such animal models in translational research across species. AD pathology is now estimated to begin at least 10–20 years before clinical symptoms, and imaging and cerebrospinal fluid biomarkers are leading the way in assessing the disease progression at a stage where neuronal damage has already occurred. Here, we emphasize the relevance of assessing early disruptions in network connectivity and plasticity that occur before neuropathological damage and progressive memory dysfunction, which can have high translational value for discovery of pre-symptomatic AD biomarkers and early mechanism-based disease interception therapeutics.