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

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 MS4A 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 MS4A variant carriers and for which MS4A4A is the major regulator. The protective variant increases MS4A4A expression and shifts the chemokine microglia subpopulation to an interferon state, while the risk variant suppresses MS4A4A expression and reduces this subpopulation of microglia. Our findings provide a mechanistic explanation for the AD variants in the MS4A locus. Further, they pave the way for future mechanistic studies of AD variants and potential therapeutic strategies for enhancing microglia resilience in AD pathogenesis. ### Competing Interest Statement M. Kampmann is an inventor on US Patent 11,254,933 related to CRISPRi and CRISPRa screening, serves on the Scientific Advisory Boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience and Alector, and is an advisor to Modulo Bio and Recursion Therapeutics. L. Piccio received research grant funding from Alector. ### Funding Statement Funding provided by the National Institutes of Health (AG067764, AG005681, AG062734, AG032438, AG058501, AG071706, NS118146 and NS127211), Hope Center for Neurological Disorders, Chan Zuckerberg Initiative (CMK, OH, MK), Thome Memorial Foundation, BrightFocus Foundation, and UL1TR002345, Alzheimer's Association ZEN-22-969903 (MK). The recruitment and clinical characterization of Knight ADRC research participants at Washington University were supported by NIH P30AG066444 (JCM), P01AG03991 (JCM), and P01AG026276 (JCM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ROSMAP (Synapse ID = Syn3219045) and Mayo (Synapse ID = Syn5550404) datasets were downloaded from AMP-AD Knowledge Portal (). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in this study is from publicly available sources. All data produced in the present study are available upon reasonable request to the authors.