Nassan Malik, Daghlas Iyas, Diamond Bram R, Martersteck Adam, Rogalski Emily
Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL 60611, USA.
Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA.
Brain Commun. 2025 Mar 4;7(2):fcaf098. doi: 10.1093/braincomms/fcaf098. eCollection 2025.
Alterations of resting state intrinsic functional networks have been associated with neurodegenerative diseases even before the onset of cognitive symptoms. Emerging hypotheses propose a role of resting state intrinsic functional networks alterations in the risk or vulnerability to neurodegeneration. It is unknown whether intrinsic functional network alterations can be causal for neurodegenerative diseases. We sought to answer this question using two-sample Mendelian randomization. Using the largest genome-wide association study of resting state intrinsic functional connectivity ( = 47 276), we generated genetic instruments (at the significance level 2.8 ×10) to proxy resting state intrinsic functional network features. Based on the known brain regions implicated in different neurodegenerative diseases, we generated genetically proxied resting state intrinsic functional features and tested their association with their paired neurodegenerative outcomes: features in parieto-temporal regions and Alzheimer dementia (111 326 cases, 677 663 controls); frontal region and frontotemporal dementia (2154 cases, 4308 controls); temporal pole region and semantic dementia (308 cases, 616 controls), and occipital region with Lewy body dementia (LBD) (2591 cases, 4027 controls). Major depressive disorder outcome (170 756 cases, 329 443 controls) was included as a positive control and tested for its association with genetically proxied default mode network (DMN) exposure. Inverse-variance weighted analysis was used to estimate the association between the exposures (standard deviation units) and outcomes. Power and sensitivity analyses were completed to assess the robustness of the results. None of the genetically proxied functional network features were significantly associated with neurodegenerative outcomes (adjusted value >0.05), despite sufficient calculated power. Two resting state features in the visual cortex showed a nominal level of association with LBD ( = 0.01), a finding that was replicated using a different instrument ( = 0.03). The genetically proxied DMN connectivity was associated with the risk of depression ( = 0.024), supporting the validity of the genetic instruments. Sensitivity analyses were supportive of the main results. This is the first study to comprehensively assess the potential causal effect of resting state intrinsic functional network features on the risk of neurodegeneration. Overall, the results do not support a causal role for the tested associations. However, we report a nominal association between visual network connectivity and Lewy body dementia that requires further evaluation.
即使在认知症状出现之前，静息态内在功能网络的改变就已与神经退行性疾病相关联。新出现的假说提出，静息态内在功能网络的改变在神经退行性变的风险或易感性中起作用。尚不清楚内在功能网络的改变是否可能是神经退行性疾病的病因。我们试图通过两样本孟德尔随机化来回答这个问题。利用最大规模的全基因组关联研究（涉及47276名受试者），我们生成了遗传工具（显著性水平为2.8×10）来代表静息态内在功能网络特征。基于与不同神经退行性疾病相关联的已知脑区，我们生成了基因代理的静息态内在功能特征，并测试了它们与配对的神经退行性疾病结局之间的关联：顶颞叶区域的特征与阿尔茨海默病痴呆（111326例病例，677663名对照）；额叶区域与额颞叶痴呆（2154例病例，4308名对照）；颞极区域与语义性痴呆（308例病例，616名对照），以及枕叶区域与路易体痴呆（LBD）（2591例病例，4027名对照）。将重度抑郁症结局（170756例病例，329443名对照）作为阳性对照，并测试其与基因代理的默认模式网络（DMN）暴露之间的关联。采用逆方差加权分析来估计暴露（标准差单位）与结局之间的关联。完成了功效和敏感性分析以评估结果的稳健性。尽管计算出的功效充足，但没有一个基因代理的功能网络特征与神经退行性疾病结局显著相关（校正P值>0.05）。视觉皮层中的两个静息态特征与LBD显示出名义上的关联水平（P = 0.01），这一发现使用不同的工具得到了重复验证（P = 0.03）。基因代理的DMN连通性与抑郁症风险相关（P = 0.024），支持了遗传工具的有效性。敏感性分析支持主要结果。这是第一项全面评估静息态内在功能网络特征对神经退行性变风险潜在因果效应的研究。总体而言，结果不支持所测试关联的因果作用。然而，我们报告了视觉网络连通性与路易体痴呆之间的名义关联，这需要进一步评估。
