03665nas a2200589   4500000000100000000000100001008004100002260001200043653002400055653002100079653002200100653002400122653001800146100001700164700002200181700002100203700002300224700001600247700001500263700001900278700001700297700002000314700001900334700001900353700001900372700001900391700001400410700001600424700001700440700001800457700002100475700002900496700002000525700001700545700002000562700001900582700002000601700002100621700002100642700001800663700002400681700002300705700001900728700002000747700001800767245007700785856005500862300001300917490000800930520212300938022001403061       2026                            d  c2026-0910aAlzheimer's disease10aBipolar disorder10aNeurodegeneration10aParkinson's disease10aSchizophrenia1 aDonghoon Lee1 aMikaela Koutrouli1 aNicolas Y. Masse1 aGabriel E. Hoffman1 aSeon Kinrot1 aXinyi Wang1 aPrashant N. M.1 aMilos Pjanic1 aTereza Clarence1 aFotios Tsetsos1 aDeepika Mathur1 aDavid Burstein1 aKaren Therrien1 aAram Hong1 aClara Casey1 aZhiping Shao1 aMarcela Alvia1 aStathis Argyriou1 aJennifer Monteiro Fortes1 aSarah R. Murphy1 aPavel Katsel1 aPavan K. Auluck1 aLisa L. Barnes1 aStefano Marenco1 aDavid A. Bennett1 aLars Juhl Jensen1 aKiran Girdhar1 aGeorgios Voloudakis1 aVahram Haroutunian1 aJaroslav Bendl1 aJohn F. Fullard1 aPanos Roussos00aSingle-cell atlas of transcriptomic vulnerability across brain disorders  uhttps://www.nature.com/articles/s41586-025-09573-z  a988-10020 v6573 aNeurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited1,2. Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual nuclei. The cohort includes neurotypical controls, as well as donors affected by eight common and complex brain disorders: Alzheimer’s disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson’s disease (PD), tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder. We show that interindividual variation accounts for a substantial portion of gene expression variation. By comparing transcriptomic variation across diseases, we reveal universal signatures enriched in basic cellular functions such as mRNA processing and protein localization. After discounting these cross-disease signatures, we show stronger genetic and transcriptomic concordance among AD, DLBD, Vas and PD. Furthermore, we characterize transcriptomic variation among different AD phenotypes, distinct from those observed in healthy ageing, revealing a reduction in neuronal abundance in individuals with more severe AD, coupled with an increase in immune and vascular cell populations. Exploring the neuropsychiatric symptoms (NPSs) that frequently accompany AD, we find an increased abundance of deep-layer excitatory neurons associated with a broad range of NPSs. By constructing transcriptome trajectories that capture AD progression, we implicate cell-type-specific responses in the early and late stages of AD. Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological–immune–vascular systems, and identifying potential targets for therapeutic intervention.  a1476-4687