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

Abstract

AbstractGenome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in theMS4Alocus (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 inMS4Avariant carriers and for whichMS4A4Ais the major regulator. The protective variant increasesMS4A4Aexpression and shifts the chemokine microglia subpopulation to an interferon state, while the risk variant suppressesMS4A4Aexpression and reduces this subpopulation of microglia. Our findings provide a mechanistic explanation for the AD variants in theMS4Alocus. Further, they pave the way for future mechanistic studies of AD variants and potential therapeutic strategies for enhancing microglia resilience in AD pathogenesis.