{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:47:26Z","timestamp":1782539246044,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Despite extensive investments in Alzheimer's disease (AD) therapeutic development, progress toward effective interventions remains modest. The landscape of potential novel therapeutic strategies is rapidly growing, but prioritization, validation, and tools to advance targets to trial are lagging. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT\u2010AD) consortium has integrated systems\u2010level data from large\u2010scale studies profiling thousands of human brains, yielding target\u2010specific risk scores that partition disease risk into discrete biological domains and enable data\u2010driven target interrogation. Here, we compared clinical trial targets with top\u2010ranked TREAT\u2010AD targets and found a limited overlap as well as differences in the biology emphasized by each set. The current AD therapeutic development landscape remains largely under the \u201cstreetlight\u201d of familiar biology, while unbiased measures of disease risk point toward other disease\u2010associated processes that remain comparatively underexplored. These findings underscore opportunities to more deliberately diversify therapeutic portfolios and complement existing development efforts with evidence derived from unbiased human data.<\/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>Clinical AD trials remain focused on well\u2010characterized biology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TREAT\u2010AD integrates genetic and multi\u2010omic data to prioritize novel targets.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Limited overlap exists between clinical and high\u2010risk data\u2010driven targets.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Risk\u2010associated targets uniquely implicate mitochondrial, lipid, and other pathways.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Advancing \u201cdark\u201d targets is critical to diversify AD therapeutic strategies.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71142","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:56:02Z","timestamp":1770976562000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond the streetlight: a TREAT\u2010AD perspective on where to find new Alzheimer's targets"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3573-5229","authenticated-orcid":false,"given":"Gregory A.","family":"Cary","sequence":"first","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse C.","family":"Wiley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Toxicology University of Kansas Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory W.","family":"Carter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan I.","family":"Levey","sequence":"additional","affiliation":[{"name":"Goizueta Brain Health Institute and Alzheimer's Disease Research Center Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","unstructured":"Alzheimer's Association 2025 Alzheimer's Disease Facts and Figures n.d. doi:10.1002\/alz.70235","DOI":"10.1002\/alz.70235"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70098"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.105"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12461"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12465"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12385"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12295"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12179"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12050"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2019.05.008"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2018.03.009"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2017.05.002"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2016.07.001"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa840"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/amiajnl\u20102011\u2010000116"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1059"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1004"},{"key":"e_1_2_7_19_1","unstructured":"Herv\u00e9 Pag\u00e8sMC.AnnotationDbi.2017. doi:10.18129\/B9.BIOC.ANNOTATIONDBI"},{"key":"e_1_2_7_20_1","unstructured":"CarlsonM.org.Hs.eg.db.2017. doi:10.18129\/B9.BIOC.ORG.HS.EG.DB"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.2307\/2346101"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2016.1135132"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010024\u201001020\u2010z"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1033"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010021\u201000862\u20100"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010230899"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007316\u20100"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010025\u201001349\u2010z"}],"container-title":["Alzheimer's &amp; 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