Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Analysis Reveals Immune Cell-Specific Mechanisms in Alzheimer's Disease

This medRxiv preprint reports a single-cell eQTL Mendelian randomisation and colocalisation analysis in Alzheimer's disease, finding a shared genetic signal between TNF expression in CD4+SOX4+ T cells and disease risk at a posterior probability of 0.833, while noting that the instrument's phenome-wide associations were confined to immune and haematological traits with no genome-wide significant neurological phenotype. Claidex holds three TNF failures, all carrying the efficacy archetype: inb03-soluble-tnf-covid19-ards-futility, balinatunfib-sar441566-tnf-tnfr1-crohns-disease-phase2-program-termination, and balinatunfib-sar441566-tnf-ulcerative-colitis-specifi-uc-phase2-interim-efficacy-termination. Severity computes to STRONG because three prior failures share that archetype, and the rule cross-references on target gene alone. The diseases differ, and TNF inhibitors missing endpoints in colitis, Crohn's disease and acute respiratory distress do not refute a genetic association in Alzheimer's disease. The narrower caution the record supports is that TNF has repeatedly produced human genetic and expression associations that did not convert into clinical benefit once the pathway was blocked pharmacologically, and the authors' own null for neurological phenotypes points the same way.