{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:03:42Z","timestamp":1790337822976,"version":"4.1.0"},"reference-count":57,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82272583"],"award-info":[{"award-number":["No. 82272583"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dementia subtypes exhibit diverse clinical and pathological features, yet may share convergent molecular underpinnings. Identifying these common pathways is critical for unified therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To delineate the shared genetic architecture and convergent molecular pathways underlying diverse dementia subtypes, and to mechanistically characterize the structural and functional impacts of key risk variants, thereby establishing a unified framework for precision therapeutic development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied multivariate genomic structural equation modeling to six dementia-related genome-wide association studies (GWAS), followed by integrative transcriptome-wide association studies (TWAS) across tissues and cell types. We combined AlphaFold3-predicted structures, molecular dynamics simulations, and deep learning\u2013based stability analyses to assess functional impacts of risk variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We uncovered a shared genetic architecture underlying dementia, identifying 60 novel risk loci.\n                      <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                      emerged as the central hub, linking lipid metabolism and immune dysregulation. Missense variants in\n                      <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                      (p.Arg176Cys),\n                      <jats:italic toggle=\"yes\">BIN2<\/jats:italic>\n                      (p.Glu190Lys), and\n                      <jats:italic toggle=\"yes\">FOXO1<\/jats:italic>\n                      (p.Asp82His\/Tyr\/Asn) induced charge-dependent conformational destabilization, impairing lipid transport, microglial phagocytosis, and transcriptional control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our multiscale framework bridges population genetics with molecular pathophysiology, establishing\n                      <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                      -centered transcriptional dysregulation as a unifying mechanism in dementia. These findings nominate convergent pathways, particularly lipid-immune crosstalk, as high-priority targets for precision therapeutics.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261489800","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:11:48Z","timestamp":1790165508000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>APOE<\/i>\n                    -centered transcriptional convergence underlying diverse dementia subtypes"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0473-4349","authenticated-orcid":false,"given":"Zhi-Jie","family":"Xu","sequence":"first","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-7923","authenticated-orcid":false,"given":"Jie","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7271-1229","authenticated-orcid":false,"given":"Guido M.","family":"Giuffr\u00e8","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy"},{"name":"Fondazione Policlinico Agostino Gemelli IRCCS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7515-3958","authenticated-orcid":false,"given":"Jia-Jia","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0087-5156","authenticated-orcid":false,"given":"Xin","family":"Xue","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-2917","authenticated-orcid":false,"given":"Juan-Juan","family":"Lu","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2665-534X","authenticated-orcid":false,"given":"Paolo Maria","family":"Rossini","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Roma"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2935-7551","authenticated-orcid":false,"given":"Xu-Yun","family":"Hua","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0601-3403","authenticated-orcid":false,"given":"Jian-Guang","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Shanghai University of Traditional Chinese Medicine"},{"name":"Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_3_3_2_2","article-title":"A systematic exposure-wide framework leveraging machine learning to identify multidomain exposure factors and their joint influence on cognitive function: evidence from a neurological cohort","volume":"21","author":"Wu J","year":"2025","unstructured":"Wu J, Yin B, Wen R, et al. 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