Molecular signatures of resilience to Alzheimer’s disease in neocortical layer 4 neurons

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 App SAA 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.