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Cleavage at the cell surface releases soluble SORL1 (sSORL1) into cerebrospinal fluid (CSF). We examined whether CSF\u2010sSORL1 can serve as an in vivo marker of genetically impaired SORL1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      CSF\u2010sSORL1 was quantified by enzyme\u2010linked immunosorbent assay (ELISA) in 218 participants: 90 carriers of\n                      <jats:italic>SORL1<\/jats:italic>\n                      variants, 78\n                      <jats:italic>SORL1<\/jats:italic>\n                      \u2010wildtype (WT) AD patients, and 50\n                      <jats:italic>SORL1<\/jats:italic>\n                      \u2010WT controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      sSORL1 concentrations were significantly lower in carriers of protein\u2010truncating and damaging missense variants. In\n                      <jats:italic>SORL1<\/jats:italic>\n                      \u2010WT patients, CSF\u2010s\n                      <jats:italic>SORL1<\/jats:italic>\n                      correlated with pTau181 but not with A\u03b242 among AD patients, and did not differ between patients and controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings suggest that impaired SORL1 trafficking reduces receptor delivery to the cell surface and thereby decreases sSORL1 shedding, supporting its potential use as a pathway\u2010specific biomarker.<\/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>Enzyme\u2010linked immunosorbent assay (ELISA) enables quantitative measurement of soluble sortilin\u2010related receptor (sSORL1) in cerebrospinal fluid (CSF).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            sSORL1 levels are reduced in CSF from carriers of a pathogenic\n                            <jats:italic>SORL1<\/jats:italic>\n                            variant.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CSF\u2010sSORL1 levels correlate with tau pathology in Alzheimer's disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>sSORL1 levels represent an in vivo biomarker of SORL1 function.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71042","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T10:25:13Z","timestamp":1770978313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Soluble SORL1 in cerebrospinal fluid as a marker for functional impact of rare\n                    <i>SORL1<\/i>\n                    variants"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-4326","authenticated-orcid":false,"given":"Matthijs W. J.","family":"de Waal","sequence":"first","affiliation":[{"name":"Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam UMC Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Neurodegeneration Amsterdam Neuroscience Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven J.","family":"van der Lee","sequence":"additional","affiliation":[{"name":"Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Amsterdam UMC Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Neurodegeneration Amsterdam Neuroscience Amsterdam The Netherlands"},{"name":"Alzheimer Center Amsterdam, Neurology, Amsterdam UMC Vrije Universiteit Amsterdam  Amsterdam The 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Monti","sequence":"additional","affiliation":[{"name":"Dept. of Biomedicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Mette G.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Dept. of Biomedicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian B.","family":"Vaegter","sequence":"additional","affiliation":[{"name":"Dept. of Biomedicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Raska","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine Masaryk University  Brno Czech Republic"},{"name":"International Clinical Research Center St. Anne's Faculty Hospital  Brno Czech 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