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通过与代谢标志物的基因重叠揭示阿尔茨海默病和帕金森病独特的代谢特征。

Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap with metabolic markers.

作者信息

Stinson Sara E, Shadrin Alexey A, Rahman Zilur, Rødevand Linn, Broce Iris J, Persson Karin, Selbæk Geir, Stefansson Hreinn, Haavik Jan, Parker Nadine, Koch Elise, Frei Oleksandr, O'Connell Kevin S, Smeland Olav B, Djurovic Srdjan, Dale Anders M, van der Meer Dennis, Andreassen Ole A

出版信息

medRxiv. 2025 Jul 31:2025.07.31.25332114. doi: 10.1101/2025.07.31.25332114.

DOI:10.1101/2025.07.31.25332114
PMID:40766152
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12324630/
Abstract

Metabolic dysfunction is increasingly implicated in neurodegenerative diseases, yet the genetic architecture linking metabolic markers with Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear. We systematically analysed phenotypic and genetic relationships between 249 circulating metabolites with AD and PD, comparing patterns to body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Using linkage disequilibrium score regression and bivariate Gaussian mixture modeling, we identified distinct genetic overlap. AD correlated positively with cardiometabolic traits (BMI, r =0.11; T2D, r =0.23; CAD, r =0.22; stroke, r =0.18), whereas PD showed opposing patterns (AD-PD r =-0.36). Mendelian randomization identified bi-directional causal effects of lipid measures on AD and divergent effects of glutamine on AD and PD. Conjunctional FDR analyses mapped 1,377 shared genes, implicating lipid metabolism in AD and synaptic processes in PD. These findings disentangle disease-specific pathways and inform therapeutic strategies targeting metabolic health.

摘要

代谢功能障碍与神经退行性疾病的关联日益密切，然而，将代谢标志物与阿尔茨海默病（AD）和帕金森病（PD）联系起来的遗传结构仍不清楚。我们系统地分析了249种循环代谢物与AD和PD之间的表型和遗传关系，并将其模式与体重指数（BMI）、2型糖尿病（T2D）、冠状动脉疾病（CAD）和中风进行了比较。使用连锁不平衡评分回归和双变量高斯混合模型，我们确定了不同的遗传重叠。AD与心脏代谢特征呈正相关（BMI，r = 0.11；T2D，r = 0.23；CAD，r = 0.22；中风，r = 0.18），而PD则呈现相反的模式（AD-PD r = -0.36）。孟德尔随机化确定了脂质指标对AD的双向因果效应以及谷氨酰胺对AD和PD的不同效应。联合错误发现率分析确定了1377个共享基因，表明脂质代谢与AD有关，而突触过程与PD有关。这些发现厘清了疾病特异性途径，并为针对代谢健康的治疗策略提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/33b015d1d92d/nihpp-2025.07.31.25332114v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/e23af53afdf2/nihpp-2025.07.31.25332114v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/744fe1fab0a0/nihpp-2025.07.31.25332114v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/33b015d1d92d/nihpp-2025.07.31.25332114v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/e23af53afdf2/nihpp-2025.07.31.25332114v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/8f5d0e3530ae/nihpp-2025.07.31.25332114v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/4f7d647cf58e/nihpp-2025.07.31.25332114v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/0ba2ff027278/nihpp-2025.07.31.25332114v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/744fe1fab0a0/nihpp-2025.07.31.25332114v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d0a/12324630/33b015d1d92d/nihpp-2025.07.31.25332114v1-f0006.jpg

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