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Cerebrospinal fluid proteomic associations of APOE genotypes reveal distinct protective and risk mechanisms for Alzheimer's disease

Abstract 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 untargete...

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Main Authors: Vromen, Eleonora M. (Author) , Lageman, Senne B. (Author) , Gobom, Johan (Author) , van der Kant, Rik (Author) , Dobricic, Valerija (Author) , Bertram, Lars (Author) , Streffer, Johannes (Author) , Lovestone, Simon (Author) , Vos, Stephanie J. B. (Author) , Tainta, Mikel (Author) , Freund-Levi, Yvonne (Author) , Frölich, Lutz (Author) , Popp, Julius (Author) , Peyratout, Gwendoline (Author) , Tsolaki, Magda (Author) , Verhey, Frans (Author) , Vandenberghe, Rik (Author) , Schaeverbeke, Jolien (Author) , Blennow, Kaj (Author) , van der Lee, Sven J. (Author) , Scheltens, Philip (Author) , Pijnenburg, Yolande A. L. (Author) , van der Flier, Wiesje M. (Author) , Teunissen, Charlotte E. (Author) , Zetterberg, Henrik (Author) , Visser, Pieter Jelle (Author) , Tijms, Betty (Author)
Format: Article (Journal)
Language:English
Published: October 2025
In: Alzheimer's and dementia
Year: 2025, Volume: 21, Issue: 10, Pages: 1-13
ISSN:1552-5279
DOI:10.1002/alz.70738
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/alz.70738
Verlag, kostenfrei, Volltext: https://alz-journals-onlinelibrary-wiley-com.ezproxy.medma.uni-heidelberg.de/doi/10.1002/alz.70738
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Author Notes: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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Summary:Abstract 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.
Item Description:Erstmals veröffentlicht: 14. Oktober 2025
Gesehen am 08.01.2026
Physical Description:Online Resource
ISSN:1552-5279
DOI:10.1002/alz.70738

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