Inflammation is a primary component of age-related neurodegenerative diseases. Immense effort has been dedicated to understanding central inflammatory responses in neurodegeneration. Yet, peripheral immune changes remain incompletely understood. Utilizing single-cell transcriptome analysis of 560,000 peripheral blood mononuclear cells from 118 individuals with clinical neurodegeneration compared to 101 cognitively typical controls, we uncover marked alterations to peripheral immunity. These molecular signatures are both unique to, and shared between, Alzheimer’s and Parkinson’s diseases. Likewise, different immune cell types partially share diseases-specific components.