{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:10:11Z","timestamp":1791925811110,"version":"4.3.4"},"reference-count":80,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      The strongest genetic drivers of late\u2010onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      . Despite their critical roles, the mechanisms underlying their interactions remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We conducted microsecond\u2010long molecular dynamics simulations of TREM2\u2010ApoE complexes, including TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      , validating our findings through comparison with published experimental data on TREM2\u2010ApoE binding interactions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Our simulations reveal TREM2\n                      <jats:sup>WT<\/jats:sup>\n                      can sample an \u201copen\u201d CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2\n                      <jats:sup>WT<\/jats:sup>\n                      exhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      \u2019s CDR2 may explain its reduced ligand\u2010binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2\u2010ApoE2 complexes, which is absent with ApoE4. TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      and ApoE4 mutually rigidify each other, suppressing interfacial flexibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Our findings suggest mechanisms underlying ApoE2's neuroprotective functions, ApoE4's pathogenicity, and the synergistic effects of ApoE4 and TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      in AD. TREM2\n                      <jats:sup>WT<\/jats:sup>\n                      \u2019s flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2\n                      <jats:sup>R47H<\/jats:sup>\n                      \u2010ApoE4 interactions may drive pathogenic signaling.\n                    <\/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>\n                            TREM2\n                            <jats:sup>WT<\/jats:sup>\n                            samples diverse CDR2 conformations, challenging prior assumptions that an \u201copen\u201d CDR2 state is solely pathogenic.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            ApoE2 promotes dynamic reconfiguration of TREM2\u2010ApoE2 complexes, preserving TREM2\n                            <jats:sup>WT<\/jats:sup>\n                            's flexibility.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The TREM2\n                            <jats:sup>R47H<\/jats:sup>\n                            \u2010ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70120","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T06:23:46Z","timestamp":1744439026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Synergistic reduction in interfacial flexibility of TREM2\n                    <sup>R47H<\/sup>\n                    and ApoE4 may underlie AD pathology"],"prefix":"10.1002","volume":"21","author":[{"given":"Emma E.","family":"Lietzke","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder Colorado USA"},{"name":"Division of Endocrinology Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Saeb","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma C.","family":"Aldrich","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley D.","family":"Bruce","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7505-7920","authenticated-orcid":false,"given":"Kayla G.","family":"Sprenger","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"issue":"10","key":"e_1_2_8_3_1","article-title":"The genetics of Alzheimer disease. 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