Wei Xiangzan, Qin Weirong
Education Department of Guangxi Zhuang Autonomous Region, Key Laboratory of Biological Molecular Medicine Research (Guangxi Medical University), Nanning, P. R. China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, P.R. China.
J Alzheimers Dis Rep. 2025 Jun 30;9:25424823251348844. doi: 10.1177/25424823251348844. eCollection 2025 Jan-Dec.
Resting-state functional magnetic resonance imaging (rsfMRI) is pivotal for mapping alterations in brain functional networks associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, the causal mechanisms linking such network dysfunction to disease pathogenesis remain unresolved.
This study aimed to elucidate bidirectional causal relationships between 191 resting-state fMRI phenotypes (derived from 34,691 individuals) and six neurodegenerative diseases, specifically AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), using disease-specific GWAS data from European-ancestry cohorts.
Bidirectional two-sample Mendelian randomization (MR) was performed using rsfMRI phenotypes from Zhao et al. (2022) and GWAS summary statistics (AD: ieu-b-5067/ebi-a-GCST90027158, ALS: ebi-a-GCST90027164, FTD: ieu-b-43, MS: ieu-b-18, DLB: ebi-a-GCST90001390, PD: ieu-b-7). Instrumental variables were filtered for significance (p < 5 × 10^-8), with sensitivity analyses (MR-PRESSO, Cochran's Q, MR-Egger) to ensure robustness.
Forward MR identified 26 rsfMRI phenotypes causally linked to neurodegenerative diseases. AD risk was associated with reduced cerebellum-subcortical connectivity (OR = 0.957, p = 0.004), while heightened cerebellar activity increased DLB risk (OR = 2.58, p = 0.0063). Reverse MR revealed 64 disease-to-network effects: AD altered default mode network connectivity (OR = 0.965, p = 0.034), and PD disrupted salience-central executive network interactions (OR = 0.950, p = 0.00011).
This study establishes robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases, with AD showing unique vulnerability in cerebellar-subcortical and default mode circuits. These findings highlight network-specific therapeutic targets for AD and related disorders.
静息态功能磁共振成像（rsfMRI）对于描绘与神经退行性疾病，特别是阿尔茨海默病（AD）相关的脑功能网络变化至关重要。然而，将这种网络功能障碍与疾病发病机制联系起来的因果机制仍未得到解决。
本研究旨在利用欧洲血统队列的疾病特异性全基因组关联研究（GWAS）数据，阐明191种静息态fMRI表型（来自34,691名个体）与六种神经退行性疾病之间的双向因果关系，这六种疾病分别为AD、肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）、多发性硬化症（MS）、路易体痴呆（DLB）和帕金森病（PD）。
使用Zhao等人（2022年）的rsfMRI表型和GWAS汇总统计数据（AD：ieu-b-5067/ebi-a-GCST90027158，ALS：ebi-a-GCST90027164，FTD：ieu-b-43，MS：ieu-b-18，DLB：ebi-a-GCST90001390，PD：ieu-b-7）进行双向两样本孟德尔随机化（MR）。对工具变量进行显著性过滤（p < 5 × 10^-8），并进行敏感性分析（MR-PRESSO、 Cochr an's Q、MR-Egger）以确保稳健性。
正向MR确定了26种与神经退行性疾病有因果关系的rsfMRI表型。AD风险与小脑-皮质下连接性降低有关（OR = 0.957，p = 0.004），而小脑活动增强增加了DLB风险（OR = 2.58，p = 0.0063）。反向MR揭示了64种疾病对网络的影响：AD改变了默认模式网络连接性（OR = 0.965，p = 0.034），PD破坏了突显-中央执行网络相互作用（OR = 0.950，p = 0.00011）。
本研究建立了脑功能网络与神经退行性疾病之间强大的双向因果途径，AD在小脑-皮质下和默认模式回路中表现出独特的易损性。这些发现突出了AD及相关疾病的网络特异性治疗靶点。
