Abstract

Neurodegenerative disease is largely driven by pathological protein states, which cannot be fully inferred from transcript levels. Yet, joint measurement of cytoplasmic proteins and RNA in single cells from archival human brain tissue remains challenging. Here we present Soma-seq, a method integrating transcriptome and antibody-based intracellular protein measurements in single cells from frozen human brain tissue. Applying Soma-seq to Alzheimer's disease cortex, we quantified multiple intracellular proteins, including hyperphosphorylated Tau, alongside RNA. Soma-seq resolves a continuous trajectory of pathological progression based on multiplexed protein measurements and reveals associated gene programs. CRISPR perturbation in human iPSC-derived neurons validates Soma-seq-derived candidates and identifies protective factors to Tau aggregation.