A Scalable Human Brain Cell Atlas Foundation Model Dissects the Cellular Immune Codes and Cognitive Resilience

The biological basis of resilience to cognitive decline and Alzheimer’s disease (AD) remains unclear, hindering the development of effective interventions for brain health. Here, we present the largest human brain single-nucleus RNA-seq atlas to date (~14 million nuclei across 31 brain regions from 2,239 deeply phenotyped postmortem samples, including cognitively normal (CN), AD (clinico-pathologically confirmed), cognitively resilient (CR), and primary age-related tauopathy (PART)), using a scalable single-cell foundation model. This resource identifies >50 neuronal and glial cell types and reveals mitochondrial bioenergetics in somatostatin (SST) neurons linked to cognitive resilience despite amyloid-beta/tau pathology, which we validated immunohistochemically. Age-related downregulation of protective genes (i.e., PLCG2) and upregulated pro-inflammatory signals (TGF-β, IL18) in microglia drove AD progression, with female-specific markers (USP18, IFIT3) linked to microglial state transition (i.e., disease-associated microglia). Glutamate-mediated T cell-microglia crosstalk and proliferative microglia mediated complement signaling are associated with AD pathogenesis. Integrating deep clinical and genomic data under the single-cell foundation model, this comprehensive brain cell atlas deciphers brain-immune interactions underlying brain resilience and offers an open-access platform to accelerate therapies for neurodegeneration.