Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs. It facilitates the identification of interacting proteins that significantly influence mutant TDP-43 and HTT toxicity in transgenic flies, as well as of ARF-GEP100 that controls misfolding and aggregation of multiple ND-causing proteins in experimental model systems. Furthermore, it enables the prediction of ND-specific subnetworks and the identification of proteins, such as ATXN1 and MKL1, that are abnormally aggregated in postmortem brains of Alzheimer’s disease patients, suggesting widespread protein aggregation in NDs. Display omitted •A map of ∼30,000 connections of ∼5,000 human proteins relevant to neurodegeneration•Network approach identifies modifiers of mutant TDP-43 and HTT toxicity in flies•ARF-GEP100 controls misfolding and aggregation of disease-causing proteins•MKL1 and ataxin-1 abnormally aggregate in AD patient brains Haenig et al. present an interactome network of ∼30,000 connections among ∼5,000 proteins involved in neurodegenerative diseases. The network highlights proteins that influence aggregation and toxicity of known disease-causing proteins and predicts disease-specific subnetworks and new proteins found to be abnormally aggregated in AD patient brains.