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Common variants in\n                      <jats:italic>MS4A4A<\/jats:italic>\n                      affect AD susceptibility, gene expression, triggering receptor expressed on myeloid cells 2 (TREM2) signaling, and microglial transcriptional states, but the gene's functional role remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Using a novel model, we investigated the impact of\n                      <jats:italic>Ms4a4a<\/jats:italic>\n                      loss in the 5xFAD mouse model of amyloid beta (A\u03b2) accumulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Ms4a4a<\/jats:italic>\n                      deficiency reduced steady\u2010state A\u03b2 levels and shortened its half\u2010life in brain interstitial fluid. Aged 5xFAD mice lacking\n                      <jats:italic>Ms4a4a<\/jats:italic>\n                      exhibited more compact plaques and lower overall plaque burden. Microglia deficient in\n                      <jats:italic>Ms4a4a<\/jats:italic>\n                      showed a pro\u2010inflammatory profile and elevated matrix metalloproteinase 9 (MMP\u20109) production, which may facilitate A\u03b2 degradation. Notably, human carriers of the AD\u2010resilient variant rs1582763 near\n                      <jats:italic>MS4A4A<\/jats:italic>\n                      also displayed increased cerebrospinal fluid MMP\u20109 levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Together, we show that\n                      <jats:italic>Ms4a4a<\/jats:italic>\n                      loss enhances A\u03b2 clearance and reduces pathology, suggesting a protective mechanism that may inform microglia\u2010targeted AD therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            We examined the impact of\n                            <jats:italic>Ms4a4a<\/jats:italic>\n                            loss on amyloid beta (A\u03b2) pathology using a mouse model of A\u03b2 accumulation (5xFAD).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>Ms4a4a<\/jats:italic>\n                            loss reduces overall plaque burden and increases plaque compaction.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Microglia lacking\n                            <jats:italic>Ms4a4a<\/jats:italic>\n                            are more pro\u2010inflammatory and produce more matrix metalloproteinase 9 (MMP\u20109).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Alzheimer's disease (AD) resilience variant carriers,\n                            <jats:italic>MS4A4A<\/jats:italic>\n                            rs1582763, exhibit significantly elevated levels of cerebrospinal fluid MMP\u20109.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Our findings suggest that reduction of\n                            <jats:italic>MS4A4A<\/jats:italic>\n                            may be a therapeutic approach for AD.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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