Multi-Cohort Transcriptomic Integration Identifies Overlapping Immune and Antigen-Presentation Features in Alzheimer’s Disease and Hashimoto’s Thyroiditis
TL;DR
AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues, and these overlapping features are associative and do not establish a causal relationship between AD and HT.
Abstract
Background: Thyroid disorders and Alzheimer’s disease (AD) have been linked epidemiologically, but whether AD brain tissue and thyroid tissue affected by Hashimoto’s thyroiditis (HT) share molecular features remains unclear. Methods: Differential expression was estimated in AD (GSE122063) and HT (GSE138198) discovery cohorts using limma, with donor-level blocking and adjustment for age, sex and post-mortem interval where available. Shared genes were tested against chance within the genes measured in both cohorts, separately for each direction of change; characterized by enrichment analysis; related to marker-based cell-state scores; and evaluated in two AD cohorts, three thyroid cohorts including one with concurrently collected normal thyroid (GSE165724), and a single-nucleus AD dataset (GSE138852). Results: The discovery analyses identified 3593 AD- and 3806 HT-associated genes. The overlap was direction-specific: genes upregulated in both diseases exceeded chance (117 vs. 83.2 expected; p = 8.9 × 10−5), whereas the other direction combinations did not. Co-upregulated genes were enriched for MHC class II antigen presentation (FDR = 0.004), complement (FDR = 0.002), microglial activation (FDR = 0.017) and T-cell activation (FDR = 1.7 × 10−4), and recurred in two independent thyroid datasets and the within-study LT+ versus LT− comparison, with less consistent, region-dependent recurrence in AD cohorts. This shared component tracked immune cell-state signals—glial/myeloid activation in AD and lymphocytic infiltration in HT. Fourteen co-upregulated genes, including ITGAX, CD22 and BST2, met prespecified recurrence and detectability criteria. Conclusions: AD brain tissue and thyroid tissue affected by HT exhibit a co-upregulated immune and antigen-presentation transcriptional program that reflects immune activation in both tissues. These overlapping features are associative and do not establish a causal relationship between AD and HT.