Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer’s disease (AD), Huntingtin (HTT) for Huntington’s disease, Parkin (PARK2) for Parkinson’s disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD. Display omitted •Quantitative interactomics of proteins involved in four neurodegenerative diseases•Differential interaction mapping of wild-type and disease-associated proteins•Interaction partners are significantly linked to disease phenotypes in vivo•Interaction of APP and LRPPRC appears to induce mitochondrial dysfunction in AD Hosp et al. show that quantitative interaction proteomics of neurodegenerative disease proteins captures interactions relevant to pathogenesis. Differential interactome mapping reveals preferential binding of the mitochondrial protein LRPPRC with an early-onset Alzheimer’s disease (AD) variant of APP, potentially contributing to mitochondrial dysfunction observed in AD.