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Dementia"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Increasing evidence has highlighted rare variants in Alzheimer's disease (AD). However, insufficient sample sizes, especially in underrepresented ethnic groups, hinder their investigation. Additionally, their impact on endophenotypes remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We prioritized rare likely\u2010deleterious variants based on whole\u2010genome sequencing data from a Chinese AD cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0988). Gene\u2010based optimal sequence kernel association tests were conducted between AD cases and normal controls to identify AD\u2010related genes. Network clustering, endophenotype association, and cellular experiments were conducted to evaluate their functional consequences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      We identified 11 novel AD candidate genes, which captured AD\u2010related pathways and enhanced AD risk prediction performance. Key genes (\n                      <jats:italic>RABEP1<\/jats:italic>\n                      ,\n                      <jats:italic>VIPR1<\/jats:italic>\n                      ,\n                      <jats:italic>RPL3L<\/jats:italic>\n                      , and\n                      <jats:italic>CABIN1<\/jats:italic>\n                      ) were linked to cognitive decline and brain atrophy. Experiments showed\n                      <jats:italic>RABEP1<\/jats:italic>\n                      p.R845W inducing endocytosis dysregulation and exacerbating toxic amyloid \u03b2 accumulation, underscoring its therapeutic potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings highlighted the contributions of rare variants to AD and provided novel insights into AD therapeutics.<\/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>Identified 11 novel AD candidate genes in a Chinese AD cohort.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Correlated candidate genes with AD\u2010related cognitive and brain imaging traits.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Indicated\n                            <jats:italic>RABEP1<\/jats:italic>\n                            p.R845W as a critical AD contributor in the endocytic pathway.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14444","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T06:29:56Z","timestamp":1734935396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Integrating rare pathogenic variant prioritization with gene\u2010based association analysis to identify novel genes and relevant multimodal traits for Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Jixin","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Neurology Zhongshan Hospital and Institute of Science and Technology for Brain\u2010Inspired Intelligence Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute for Translational Brain Research Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Yi Zac","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Chung Yuan Christian University  Taoyuan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gerontology Shanghai Jiao Tong University Affiliated Sixth People's 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