A single-cell transcriptomic atlas of the prefrontal cortex across the human lifespan

Abstract

The dorsolateral prefrontal cortex is central to higher cognitive functions and is particularly vulnerable to age-related decline. To advance our understanding of the molecular mechanisms underlying brain development, maturation, and aging, we constructed a detailed single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, encompassing over 1.3 million nuclei from 284 postmortem samples spanning the full human lifespan (0-97 years). This atlas reveals distinct phases of transcriptomic activity: a dynamic developmental period, stabilization during midlife, and subtle yet coordinated changes in late adulthood. Modeling non-linear age trends across the lifespan shows ten distinct trajectories of the entire transcriptome from all cell types, with notable findings in neurons and microglia, linked to neurodevelopmental disorders and Alzheimers disease risk, respectively. Moreover, excitatory neurons exhibit a convergence of gene expression patterns across the lifespan, suggesting the emergence of a common molecular signature of aging. Pseudotime analysis tracing the progression of cellular lineages throughout life reveals key gene clusters with dynamic expression changes that reflect development, maturation, and aging, as well as their connection to brain-related diseases. We uncover significant circadian rhythm reprogramming in late adulthood, characterized by disruption of core clock gene rhythmicity and the emergence of new rhythmic patterns, particularly within microglia and oligodendrocytes. This comprehensive single-cell atlas provides a baseline for understanding the molecular transitions from development through successful aging in the human dorsolateral prefrontal cortex.