Cross-Cohort Analysis Suggests Directional Elevation of the Neuronal Insulin-Signaling Transcriptional Program in Alzheimer's Disease

Objective

Reduced cerebral glucose metabolism is a defining feature of Alzheimer's disease (AD), and brain insulin resistance is widely invoked but defined at the level of receptor signaling, not transcript abundance. Whether the donor-level transcriptional signature of that axis rises, falls, or is unchanged in AD was examined using a cross-cohort, cell-type-resolved design with a pre-specified external test. Material and Methods: Four a-priori metabolic gene signatures (glucose delivery, astrocytic support, neuronal utilization, and insulin signaling; 123 genes fixed before any expression data were examined) were scored per nucleus within their own cell-type compartment and averaged to one value per donor in four single-nucleus RNA-seq cohorts (57 donor-level units). Effects were pooled by random-effects meta-analysis of Hedges' g (AD versus control) with the modified Hartung–K-napp estimator, complemented by a donor-label permutation test; pathway specificity was tested against 1000 size- and expression-matched random gene sets, and direction was examined at single-gene resolution and in one pre-specified external cohort.