Transcriptomic and protein analysis of human cortex reveals genes and pathways linked to NPTX2 disruption in Alzheimer's disease

The expression of NPTX2, a neuronal immediate early gene (IEG) essential for excitatory-inhibitory balance, is altered in the earliest stages of cognitive decline that precede Alzheimer's disease (AD). Here, we use NPTX2 as a point of reference to identify genes and pathways linked to its role in AD onset and progression. We performed bulk RNA sequencing on 575 middle temporal gyrus (MTG) samples across four cohorts, together with targeted proteomics in 135 of these same samples, focusing on 20 curated proteins spanning synaptic, trafficking, lysosomal, and regulatory categories. NPTX2 RNA and protein were significantly reduced in AD, and to a lesser extent in mild cognitive impairment (MCI) samples. RNA expression of BDNF, VGF, SST, and SCG2 correlated with both NPTX2 mRNA and protein levels. We identified NPTX2-correlated synaptic and mitochondrial programs that were negatively correlated with lysosomal and chromatin/stress modules. Gene set enrichment analysis (GSEA) of NPTX2 correlations across all samples confirmed broad alignment with synaptic and mitochondrial compartments, and more NPTX2-specific associations with proteostasis and translation regulator pathways, all of which were weakened in AD. In contrast, correlation of NPTX2 protein with transcriptomic profiles revealed negative associations with stress-linked transcription regulator RNAs (FOXJ1, ZHX3, SMAD5, JDP2, ZIC4), which were strengthened in AD. These results position NPTX2 as a hub of an activity-regulated "plasticity cluster" (BDNF, VGF, SST, SCG2) that encompasses interneuron function and is embedded on a neuronal/mitochondrial integrity axis that is inversely coupled to lysosomal and chromatin-stress programs. In AD, these RNA-level correlations broadly weaken, and stress-linked transcriptional regulators become more prominent, suggesting a role in NPTX2 loss of function. Individual gene-level data from the bulk RNA-seq in this study can be freely explored at [INSERT LINK].