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Here we report the successful generation of the first genetically engineered marmosets that carry knock\u2010in (KI) point mutations in the presenilin 1 (\n                      <jats:italic>PSEN1<\/jats:italic>\n                      ) gene that can be studied from birth throughout lifespan.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      CRISPR\/Cas9 was used to generate marmosets with C410Y or A426P point mutations in\n                      <jats:italic>PSEN1<\/jats:italic>\n                      . Founders and their germline offspring are comprehensively studied longitudinally using non\u2010invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non\u2010carriers. Analysis of brain revealed alterations in several enzyme\u2013substrate interactions within the gamma secretase complex prior to adulthood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Marmosets carrying KI point mutations in\n                      <jats:italic>PSEN1<\/jats:italic>\n                      provide the opportunity to study the earliest primate\u2010specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression.\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>We report the successful generation of genetically engineered marmosets harboring knock\u2010in point mutations in the PSEN1 gene.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD\u2010related biomarkers.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate\u2010specific mechanisms that drive disease progression.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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