Trauma-Derived NAMPT-Associated Transcriptional Programmes and Alzheimer’s Disease Pathology: A Cross-Context Analysis

Background: Severe trauma rapidly reprograms peripheral myeloid cells. We hypothesised that trauma-derived transcriptional programmes may exhibit distinct patterns across Alzheimer’s disease (AD) brain pathology states; this comparison does not test whether trauma exposure alters AD mechanisms or pathology. We aimed to define a reproducible NAMPT-linked trauma-response architecture and examine its associations with AD pathology axes. Methods: Trauma-responsive programmes were defined only in GSE162806 using donor-level pseudobulk analysis, assessed for replication in GSE36809 and directional preservation across NAMPT perturbation datasets, and then projected without redefinition into the SEA-AD middle temporal gyrus atlas using donor-level programme scores. Results: NAMPT increased most strongly 4 h after trauma (log2 fold change 2.53; FDR 1.45 × 10−6). A time-adjusted 350-gene NAMPT-associated network showed partial replication in GSE36809, with 82.6% directional concordance and 227/304 mapped genes meeting the prespecified replication criterion. Cross-context analysis identified SP1 and SP2 transcriptional clusters, with directional preservation supported for SP2 but not SP1. In SEA-AD (1,178,694 nuclei; 84 donors), neither the primary ADNC analysis nor the continuous MTG-local CPS analysis survived multiplicity correction. Secondary CERAD analyses showed lower NAMPT-architecture, SP1, and SP2 scores in excitatory neurons (FDR = 0.042), and the prespecified GuHCl Aβ42-plus-pTau model showed opposing conditional associations: higher Aβ42 was associated with lower programme scores, whereas higher pTau was associated with greater programme engagement. Aβ42 × pTau interactions and Micro-PVM state analyses and cognition models were not supported after correction. Conclusions: A NAMPT-associated gene network showed partial replication across trauma cohorts, while its projection into SEA-AD yielded selected, mainly excitatory-neuron pathology associations. These findings are hypothesis-generating and do not establish conserved regulatory mechanisms across peripheral myeloid and brain cells, causal effects of trauma on AD pathology, or functional recovery capacity.