Lifespan single-cell transcriptomic atlas of the human prefrontal cortex

Abstract

The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease1,2. Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal ageing and its relationship to psychiatric and neurodegenerative disorders. The dorsolateral prefrontal cortex has a central role in higher cognitive functions and is particularly sensitive to age-related decline3, yet its cellular and molecular programs across the human lifespan remain poorly defined. Most existing studies4–7 have focused on restricted age ranges or disease-affected brains, limiting the ability to distinguish normative developmental and ageing trajectories from pathological processes. Consequently, a comprehensive, lifespan-resolved reference of cellular states in the human prefrontal cortex has been lacking. Here, using a single-nucleus transcriptomic atlas spanning the human lifespan, we show that the dorsolateral prefrontal cortex exhibits non-linear, cell-type-specific transcriptional trajectories characterized by dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood. We identify distinct neuronal and glial programs, including early-life neuronal resilience pathways and late-life glial programs associated with immune activation, stress responses and circadian reorganization. These programs are anatomically organized across cortical layers and grey–white matter domains, revealing coordinated spatial and molecular changes. Together, these findings provide a framework for understanding how cellular programs transition from resilience to vulnerability in the human cortex and establish a foundation for interpreting age-related cognitive decline and disease risk. The dorsolateral prefrontal cortex exhibits non-linear, cell-type-specific transcriptional trajectories characterized by dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood.