A single-nucleus transcriptome atlas of cell diversity in human prefrontal cortex across the postnatal lifespan

Abstract

Brain aging is a major risk factor for cerebrovascular and neurodegenerative diseases, yet continuous cell-type changes across the human lifespan remain incompletely defined. Here, we integrate 15 prefrontal cortex (PFC) snRNA-seq datasets from 158 neurologically healthy donors (19–101 years) to construct an atlas of 587,878 nuclei. Using decade-wise comparisons and donor-level sensitivity analyses, we identify cell-type-specific transcriptomic remodeling across adulthood, with prominent early-adult and midlife remodeling windows. Across major cell classes, synapse-related programs tend to decline with age, while distinct subpopulations show changes at different life stages. Astrocytes in older decades display increased apoptosis- and inflammation-related programs, consistent with reactive-like states. Microglia show a later-life shift toward activated programs with elevated chemotaxis and inflammatory signaling. Integrating plasma proteomics with the atlas highlights FUT9 as a candidate plasma biomarker associated with brain aging. Our study provides a reference for prioritizing specific cell types and age windows for future anti-CNS aging interventions.