Neuronal activity and amyloid-β cause tau seeding in the entorhinal cortex in Alzheimer’s disease

The entorhinal cortex is the earliest site of tau pathology in both Alzheimer’s disease and primary age-related tauopathy, yet the mechanisms underlying this selective vulnerability remain poorly understood. Here, we use a computational model integrating neuronal activity and amyloid- β deposition with interneuronal tau transport to predict regional susceptibility to tau seeding. Using fluorodeoxyglucose PET as a measure of neuronal activity, we show that brain-wide activity patterns drive tau accumulation in the medial temporal lobe, independent of amyloid status. Incorporating amyloid PET, we further show that amyloid- β selectively amplifies tau seeding in the entorhinal cortex, aligning with its early involvement in Alzheimer’s disease. These predictions are supported by cross-subject correlation analysis, which reveals a significant association between model-derived seeding concentrations and empirical tau deposition. Our findings suggest that neuronal activity patterns shape the early landscape of tau pathology, while amyloid- β deposition creates a unique vulnerability in the entorhinal cortex, potentially triggering the pathological cascade that defines Alzheimer’s disease.