MS4A4A modifies the risk of Alzheimer disease by regulating lipid metabolism and immune response in a unique microglia state

Abstract

Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in the <i>MS4A</i> locus (rs1582763: protective and rs6591561: risk) and serve as major regulators of CSF sTREM2 levels. To understand their functional impact on AD, we used single nucleus transcriptomics to profile brains from carriers of these variants. We discovered a "chemokine" microglial subpopulation that is altered in <i>MS4A</i> variant carriers and for which <i>MS4A4A</i> is the major regulator. The protective variant increases <i>MS4A4A</i> expression and shifts the chemokine microglia subpopulation to an interferon state, while the risk variant suppresses <i>MS4A4A</i> expression and reduces this subpopulation of microglia. Our findings provide a mechanistic explanation for the AD variants in the <i>MS4A</i> locus. Further, they pave the way for future mechanistic studies of AD variants and potential therapeutic strategies for enhancing microglia resilience in AD pathogenesis.