Eleonora M. Vromen, Senne B. Lageman, Johan Gobom, Rik van der Kant, Valerija Dobricic, Lars Bertram, Johannes Streffer, Simon Lovestone, Stephanie J. B. Vos, Mikel Tainta, Yvonne Freund-Levi, Lutz Frölich, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Frans Verhey, Rik Vandenberghe, Jolien Schaeverbeke, Kaj Blennow, Sven J. van der Lee, Philip Scheltens, Yolande A. L. Pijnenburg, Wiesje M. van der Flier, Charlotte E. Teunissen, Henrik Zetterberg, Pieter Jelle Visser, Betty Tijms
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We studied <i>APOE</i> genotype effects on the cerebrospinal fluid (CSF) proteome.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across <i>APOE</i> genotypes using linear regression and characterized biological pathways.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (<i>n</i> = 32 individuals) or ε4 carriers (<i>n</i> = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Combining two cohorts enabled analysis of the rare <i>APOE</i> ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Apolipoprotein E (<i>APOE</i>) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD).</li>\n \n <li>Combining cohorts enabled analysis of rare <i>APOE</i> ε2–associated protection in AD.</li>\n \n <li>The rare ε2 genotype may confer protection through improved neuronal plasticity.</li>\n \n <li><i>APOE</i> ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism.</li>\n \n <li>These findings offer new insights into genotype-specific mechanisms in early AD.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70738","citationCount":"0","resultStr":"{\"title\":\"Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease\",\"authors\":\"Eleonora M. 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We studied <i>APOE</i> genotype effects on the cerebrospinal fluid (CSF) proteome.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. 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Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease
BACKGROUND
The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome.
METHODS
Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways.
RESULTS
Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.
DISCUSSION
Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.
Highlights
Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD).
Combining cohorts enabled analysis of rare APOE ε2–associated protection in AD.
The rare ε2 genotype may confer protection through improved neuronal plasticity.
APOE ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism.
These findings offer new insights into genotype-specific mechanisms in early AD.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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