Behavior of neural networks in culture suggest that sporadic and genetic forms of Alzheimer's disease may not be equivalent

INTRODUCTION: Alzheimer's disease (AD) research often assumes that familial and sporadic forms share a common pathogenesis. However, the cellular impacts of amyloid precursor protein (APP) mutations compared with age-related overexpression of APP or the deposition of amyloid beta (Aβ) are likely different. METHODS: Using high-density multi-electrode arrays, we compared neural activity in cultured neurons subjected to Aβ exposure or APP overexpression (via lentiviral delivery or genetic models). Effects on neuronal firing, synaptogenesis, axonal branching, and network connectivity were assessed in both developing and mature cultures. RESULTS: APP overexpression reduced individual neuron firing probability and impaired synaptogenesis and axonal branching during development. In contrast, Aβ disrupted synaptic connections in mature cultures and impaired network-level communication without blocking early structural development. DISCUSSION: These findings indicate that APP mis-regulation and Aβ toxicity contribute differently to neuronal behavior. These differences raise questions about the assumptions that familial and sporadic AD are similar if not identical conditions.