Project Summary In Alzheimer’s disease (AD), the first signs of cognitive impairment are observed many years before a clinical AD diagnosis is established, and the loss of synaptic function in AD is evident long before any substantial loss of neurons. The excessive production or accumulation of β-amyloid peptide (Aβ) has been documented to have deleterious effects on synaptic activity by various mechanisms. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of severe learning and memory deficits) may be critical for the development of new therapies for slowing down the progression of AD. However, detection of the AD-associated changes in synaptic function among cortical circuits is technically challenging, especially so if it is needed in the earliest stages of the AD process, before the formation of plaques and tangles, when changes are small and difficult to spot. Where exactly, at which cortical layer, or which synapse, one should investigate? The current assays for detecting neural circuit deficiencies in AD model animals are based on traditional electrode electrophysiology and have several practical limitations including: poor spatial resolution, blindness for cell-types, and a labor intensive nature of experiments. New technologies bring an improved temporal and spatial resolution for monitoring activity in many neurons simultaneously, thus facilitating studies on brain circuitry disruptions in neurological disorders. We propose to use GEVI imaging (multi-cell optical imaging of the membrane potential changes using genetically-encoded voltage indicators). Our hypothesis is that “synaptic and neuronal dysfunctions emerge before significant Aβ deposition and pathological tau aggregation, and can be routinely detected by affordable imaging methods”. A simple and sensitive physiological assay for detecting changes in network physiology, prior to the substantial accumulation of the amyloid plaques or reproducible behavioral deficits in learning and memory, would accelerate the investigations of the earliest cellular and molecular changes mediated by the AD pathological process. Understanding the cellular and molecular mechanisms of the early AD-associated synaptic dysfunction (before the behavioral manifestations of the learning and memory deficits) may help the development of the new therapies for slowing down the progression of the AD.