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Hundreds of therapeutic targets have been nominated through genetic and multi\u2010omic studies, but effective prioritization remains a major bottleneck.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We applied an integrative screening framework to assess 29 candidate targets from risk\u2010enriched biological domains. Using disease\u2010relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed small interfering RNA\u2013mediated perturbations followed by cellular phenotypic assays and quantitative proteomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Twenty\u2010five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown cells. Integrated proteomic analyses identified several perturbations that reversed AD\u2010associated molecular patterns. Five targets\u2014Ap2a2, Pdhb, Pdha1, Dlat, and Psmc3\u2014impacted both phenotypes and related proteomic responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>We established a scalable platform for target functional validation that bridges unbiased systems\u2010level assessments of AD risk with experimental evidence. The Emory\u2010Sage\u2010Structural Genomics Consortium\u2010Jax Center Target Enablement to Accelerate Therapy Development for Alzheimer's Disease center will prioritize further resource development for these validated targets.<\/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>A screening platform was created\u00a0to identify the most potent targets from nominated hypotheses.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Integrated analysis of cellular proteomics and assay phenotypes was performed.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targets capable of reversing disease\u2010associated proteomic signal were identified.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The most impactful targets were strongly implicated in Alzheimer's disease pathogenesis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71008","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T09:38:43Z","timestamp":1765618723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated phenotypic and proteomic screening identifies top\u2010tier Alzheimer's disease therapeutic targets"],"prefix":"10.1002","volume":"21","author":[{"given":"Gregory A.","family":"Cary","sequence":"first","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory W.","family":"Carter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"},{"name":"The Jackson Laboratory for Genomic Medicine  Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for The Emory\u2010Sage\u2010SGC\u2010JAX TREAT\u2010AD Center","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","unstructured":"2025 Alzheimer's Disease Facts and Figures.Alzhemers Dement.2025;21: (4)e70235. 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