Integrative hdWGCNA and multi-model validation identify BAIAP2 as a shared neuronal hub for cognitive impairment acrossAlzheimer's disease, diabetic encephalopathy and brain aging

Abstract Alzheimer’s disease (AD), diabetic encephalopathy (DE), and brain aging converge on cognitive decline with overlapping synaptic damage, impaired neuronal plasticity, and hippocampal circuit dysfunction. However, whether these pathological states share a unified neuronal transcriptional architecture remains largely unexplored at single-cell resolution. Integrating single-cell transcriptomic datasets related to AD, DE, and brain aging from the GEO database with high-dimensional weighted gene co-expression network analysis, we identified a conserved neuronal module and hub genes shared across the pathological conditions, pinpointing BAIAP2/IRSp53 as the sole shared neuronal core gene. In vivo , mouse models of all three cognitive disorders exhibited significant spatial memory deficits and consistent downregulation of hippocampal BAIAP2 at both the mRNA and protein levels; immunofluorescence further confirmed a widespread reduction of BAIAP2 in the hippocampal CA1, CA3, and dentate gyrus regions. In vitro , amyloid-β, metabolic stress, and senescence-inducing stimuli each recapitulated BAIAP2 suppression in SH-SY5Y neurons. Collectively, we establish BAIAP2 as a critical synaptic scaffolding hub whose disruption represents a unified neuronal substrate linking neurodegeneration, metabolic brain injury, and brain aging. These findings identify BAIAP2 as a potential target for AD-spectrum therapeutic strategies against cognitive decline.