GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324006/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324006GEOGSEfalseMEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages [scRNA-seq]Risk alleles for late-onset Alzheimer’s disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature—spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)—emerges across neurodegenerative and metabolic diseases, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C—a candidate AD risk gene—is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked AD causal variants in other loci to MEF2C-regulated regulatory regions and downstream risk genes. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a mechanism to modulate AD-relevant pathology.2026/08/06GSE324006GSM9566609GSM9566619GSM9566608GSM9566618GSM9566607GSM9566617GSM9566616GSM9566615GSM9566614GSM9566613GSM9566612GSM9566622GSM9566611GSM9566621GSM9566610GSM956662034281324006Homo sapiens[42094058]