03113nas a2200481   4500000000100000000000100001008004100002260001200043653002100055653002000076100001300096700002000109700002200129700001500151700001900166700001700185700002000202700001400222700001600236700002000252700001700272700001800289700002100307700002300328700002400351700002000375700002000395700002300415700002400438700001900462700002300481700001700504700002000521700002300541700001800564700001800582245007700600856005500677300001400732490000800746520186300754022001402617       2026                            d  c2026-0910aCognitive ageing10adata processing1 aHui Yang1 aTereza Clarence1 aMadeline R. Scott1 aXinyi Wang1 aPrashant N. M.1 aMilos Pjanic1 aSanan Venkatesh1 aAram Hong1 aClara Casey1 aSarah R. Murphy1 aZhiping Shao1 aMarcela Alvia1 aStathis Argyriou1 aAlexander Kawah Yu1 aNadejda M. Tsankova1 aPavan K. Auluck1 aStefano Marenco1 aVahram Haroutunian1 aGeorgios Voloudakis1 aJaroslav Bendl1 aColleen A. McClung1 aDonghoon Lee1 aJohn F. Fullard1 aGabriel E. Hoffman1 aKiran Girdhar1 aPanos Roussos00aLifespan single-cell transcriptomic atlas of the human prefrontal cortex  uhttps://www.nature.com/articles/s41586-026-10271-7  a1003-10150 v6573 aThe 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.  a1476-4687