Abstract
Selective neuronal vulnerability is a hallmark of Alzheimer’s disease (AD), yet the molecular basis of resilience remains poorly understood. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex, precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex shared molecular signatures of resilience. Early-stage resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotection (GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, CSMD1). We identified KCNIP4, which encodes a voltage-gated potassium channel-interacting protein, as a key resilience factor consistently upregulated during early stages of AD pathology. AAV-mediated overexpression of Kcnip4 in male AppSAA mice reduced the expression of activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a resource for investigating mechanisms underlying resilience to neurodegeneration.
Data availability
The raw snRNA-seq data, associated metadata, and processed digital expression matrices have been deposited at the NCBI’s Gene Expression Omnibus with accession number GSE263468. Eight of 243 samples were included in previous studies (GSE129308 and GSE181715). The snRNA-seq datasets are publicly available for interactive viewing and exploration on the Cellxgene platform at https://cellxgene.cziscience.com/collections/0d35c0fd-ef0b-4b70-bce6-645a4660e5fa. The Xenium dataset is publicly available at Zenodo: https://zenodo.org/records/16703438. Source data are provided with this paper.
Code availability
The scripts and the pretrained models are available at GitHub and accessible at Zenodo: https://doi.org/10.5281/zenodo.1811352891
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Acknowledgements
Human tissue was obtained from Stanford’s Department of Pathology and Alzheimer’s Disease Research Center (NIH/NIA P30AG066515), UCLA Department of Pathology and Easton Center, and the NIH Neurobiobank (Sepulveda repository in Los Angeles, CA and Mt. Sinai Brain Bank in New York City, NY). This work was supported by grants to I.C. from NIH/NIA (R01AG059848, R01AG082147), BrightFocus (A20173465), the Alzheimer’s Association (AARG-17-528298), and the Chan Zuckerberg Initiative (Ben Barres Early Career Acceleration Award, grant ID 199150).
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Conceptualization: S.A.P.D., I.C.; Human tissue procurement and Neuropathology: K.V., I.C.; Single-nuclear transcriptomics data generation: M.O.G., J.P.; Spatial transcriptomics data generation: J.P., J.S.R; Data analysis: S.A.P.D., W.T.; Histology: J.S.R., J.P., K.V., Y.C.L.; Functional assays in mice: J.S.R.; Funding acquisition: I.C.; Supervision: I.C.; Writing: S.A.P.D., J.S.R., I.C.; All authors read and approved the final manuscript.
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Dharshini, S.A.P., Sanz-Ros, J., Pan, J. et al. Molecular signatures of resilience to Alzheimer’s disease in neocortical layer 4 neurons. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68920-4
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DOI: https://doi.org/10.1038/s41467-026-68920-4
