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

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-10-14 DOI:10.1002/alz.70738

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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引用次数: 0

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.

Abstract Image

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APOE基因型的脑脊液蛋白质组学关联揭示了阿尔茨海默病的独特保护和风险机制

载脂蛋白E （APOE）基因包括散发性阿尔茨海默病（AD）最强的保护性（ε2）和危险性（ε4）变异，但其潜在机制尚不清楚。我们研究了APOE基因型对脑脊液（CSF）蛋白质组的影响。方法采用非靶向串联质谱法，我们分析了来自两个大队列的227名认知正常（CN）对照（A - t）、165名CN A+和177名轻度认知障碍（MCI A+）患者的脑脊液。我们使用线性回归和特征生物学途径比较了不同APOE基因型的蛋白水平。结果978个蛋白中有549个（56%）在ε2/ε3 （n = 32）或ε4携带者（n = 181）与ε3/ε3对照之间存在差异。ε2/ε3组差异最大，其中280种与神经元可塑性相关的蛋白含量较高。ε4携带者对照组显示与血脑屏障功能障碍相关的蛋白增加，A+ ε4携带者与葡萄糖代谢相关。结合两个队列可以分析罕见的APOE ε2基因型，表明保护作用可能通过改善神经元可塑性发生。载脂蛋白E （APOE）基因型在早期阿尔茨海默病（AD）中显示出不同的脑脊液蛋白质组学机制。结合队列分析了罕见的APOE ε2在AD中的相关保护作用。罕见的ε2基因型可能通过改善神经元可塑性赋予保护作用。APOE ε4携带者血脑屏障功能障碍和糖代谢增加。这些发现为早期AD的基因型特异性机制提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

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.