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We studied\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype effects on the cerebrospinal fluid (CSF) proteome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A\u2013T\u2013), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across\n                      <jats:italic>APOE<\/jats:italic>\n                      genotypes using linear regression and characterized biological pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Five hundred forty\u2010nine of 978 proteins (56%) differed between \u03b52\/\u03b53 (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a032 individuals) or \u03b54 carriers (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0181 individuals) and \u03b53\/\u03b53 controls. \u03b52\/\u03b53 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. \u03b54 carrier controls showed increased proteins linked to blood\u2013brain barrier dysfunction, and A+ \u03b54 carriers were related to glucose metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Combining two cohorts enabled analysis of the rare\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b52 genotype, suggesting protective effects may occur through improved neuronal plasticity.\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                            Apolipoprotein E (\n                            <jats:italic>APOE<\/jats:italic>\n                            ) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Combining cohorts enabled analysis of rare\n                            <jats:italic>APOE<\/jats:italic>\n                            \u03b52\u2013associated protection in AD.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The rare \u03b52 genotype may confer protection through improved neuronal plasticity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>APOE<\/jats:italic>\n                            \u03b54 carriers show increased blood\u2013brain barrier dysfunction and glucose metabolism.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These findings offer new insights into genotype\u2010specific mechanisms in early AD.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70738","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:42:39Z","timestamp":1760449359000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cerebrospinal fluid proteomic associations of\n                    <i>APOE<\/i>\n                    genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Eleonora M.","family":"Vromen","sequence":"first","affiliation":[{"name":"Alzheimer Center Amsterdam Neurology Vrije Universiteit Amsterdam Amsterdam 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