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阿尔茨海默病的遗传途径影响非痴呆个体的脑脊液生物标志物和影像学内表型。

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

机构信息

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Vrije Universiteit, Amsterdam, The Netherlands.

Amsterdam Neuroscience, Brain Imaging, Amsterdam, The Netherlands.

出版信息

Alzheimers Dement. 2024 Sep;20(9):6146-6160. doi: 10.1002/alz.14096. Epub 2024 Jul 29.

DOI:10.1002/alz.14096
PMID:39073684
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11497686/
Abstract

INTRODUCTION

Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine.

METHODS

We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity.

RESULTS

CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication.

DISCUSSION

This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies.

HIGHLIGHTS

Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

摘要

简介

揭示阿尔茨海默病（AD）遗传风险与神经病理学异质性的关系，以及这种关系是否通过特定的生物学途径发生，是迈向精准医学的关键一步。

方法

我们在非痴呆个体中计算了特定途径的遗传风险评分（GRS），并研究了 AD 风险变异如何预测反映 AD 病理学、心血管、白质完整性和大脑连接的脑脊液（CSF）和影像学生物标志物。

结果

CSF 淀粉样蛋白β和磷酸化 tau 与大多数 GRS 相关。炎症途径与脑血管疾病有关，而清除和迁移途径的定量测量白质病变和微观结构完整性的指标则与白质病变和微观结构完整性有关。功能连接改变与涉及信号转导和突触通讯的遗传变异有关。

讨论

本研究揭示了在 AD 痴呆前阶段与特定病理生理方面相关的不同遗传风险特征，揭示了 AD 相关表型异质性的生物学基础，并在疾病理解和个性化治疗的发展方面向前迈进了一步。

重点

阿尔茨海默病的多基因风险包含六个可以用特定途径的遗传风险评分来量化的生物学途径，并且与脑脊液和影像学生物标志物有不同的关联。炎症途径与脑血管负担关系最密切。白质健康与清除和膜完整性途径有关，而功能连接测量与信号转导和突触通讯途径有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/1c8c705a776f/ALZ-20-6146-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/67065d970eb4/ALZ-20-6146-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/f5dce51eacff/ALZ-20-6146-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/135024a93db7/ALZ-20-6146-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/cda42adf139b/ALZ-20-6146-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/1c8c705a776f/ALZ-20-6146-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/67065d970eb4/ALZ-20-6146-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/f5dce51eacff/ALZ-20-6146-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/135024a93db7/ALZ-20-6146-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/a6212e3171e6/ALZ-20-6146-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d27/11497686/1c8c705a776f/ALZ-20-6146-g001.jpg

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Cell type-specific roles of APOE4 in Alzheimer disease.载脂蛋白 E4 在阿尔茨海默病中的细胞类型特异性作用。
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