Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are characterized by the spread of toxic proteins through the brain, disrupting neural activity and leading to significant cognitive impairments. Despite extensive research, the mechanisms driving this spread and its impact on neuronal functioning remain poorly understood. In this talk, we present a network-based dynamical systems framework that integrates models of disease progression and neuronal activity into a unified formulation. Our computational approach (i) captures the spatio-temporal progression of disease, (ii) explains empirically-observed changes to neuronal activity, and (iii) proposes a novel role for neuronal activity in shaping disease trajectories.