In Alzheimer’s disease (AD), the amyloid-β (Aβ)-associated aggregation of tau triggers neurodegeneration and cognitive decline; hence, preventing tau aggregation is a key therapeutic target. Preclinical research found that i) Aβ precipitates neuronal hyperactivity, ii) neuronal hyperactivity promotes synaptic release of soluble hyperphosphorylated tau (p-tau) seeds, and iii) p-tau seeds spread across synapses, ensuing tau aggregation. Similarly, our research in AD patients shows that Aβ-related soluble p-tau increase mediates tau spreading across interconnected brain regions. Therefore, we hypothesize that Aβ drives neuronal hyperactivity, triggering p-tau increase, followed by connectivity mediated tau spreading in AD. Thus, attenuating Aβ-related neuronal hyperactivity may limit p-tau release, tau aggregation and cognitive decline. To test this hypothesis, we will perform a translational research project combining clinical AD datasets with neuroimaging, fluid biomarkers, electrophysiology, and patient derived neuron cell models. With these translational data, we will assess mechanistic links between Aβ, neuronal hyperactivity, ptau increase and tau spreading across connected neurons/brain regions. Our findings will be essential to assess neuronal activity as a potential treatment target (e.g. by repurposing approved anti-epileptic drugs) to prevent tau spreading, neurodegeneration and cognitive decline. This work will be instrumental for informing future clinical trials targeting neuronal hyperexcitability for disease modification in AD.