{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T18:03:17Z","timestamp":1789322597829,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,9]]},"group-title":"Neuroscience","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["U54 AG054345"],"award-info":[{"award-number":["U54 AG054345"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["R44 AG084491"],"award-info":[{"award-number":["R44 AG084491"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["R01AG079877"],"award-info":[{"award-number":["R01AG079877"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>\n                    Preclinical Alzheimer\u2019s disease (AD) research requires models with age-dependent, physiologically relevant amyloid pathology, unlike overexpression in transgenic lines. We characterized the humanized\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>SAA<\/jats:sup>\n                    knock-in model to define translationally relevant therapeutic windows.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    Homozygous\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>SAA<\/jats:sup>\n                    and control mice were evaluated from 4 to 19 months using whole-brain 3D plaque imaging, cerebral amyloid angiopathy (CAA) quantification, multiplex neuropathology, brain transcriptomics, and plasma biomarkers. Hippocampal synaptic analysis and context-dependent memory was performed at 12 months.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    Plaques, CAA, plaque-associated neuroinflammation, and dystrophic neurites accumulated with age. By 12 months, brain transcriptomes aligned with human AMP-AD co-expression modules, and plasma pTau-217, GFAP, and SNAP25 rose with age.\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>SAA<\/jats:sup>\n                    mice retained associative memory but showed memory interference and CA1 dendritic-spine loss that was exacerbated in proximity to plaques.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>SAA<\/jats:sup>\n                    mice recapitulate age-dependent, human-relevant AD phenotypes with defined therapeutic windows for preclinical research. The model is available without restriction from The Jackson Laboratory.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.08.750179","type":"posted-content","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T21:15:11Z","timestamp":1788988511000},"source":"Crossref","is-referenced-by-count":0,"title":["Characterization of the knock-in\n                  <i>App<\/i>\n                  <sup>SAA<\/sup>\n                  mouse model as a powerful tool for Alzheimer\u2019s disease preclinical research"],"prefix":"10.64898","author":[{"given":"Lucy J.","family":"Sloan","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan T.","family":"Garceau","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick 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