Kalia Vrinda, Reyes-Dumeyer Dolly, Dubey Saurabh, Nandakumar Renu, Lee Annie J, Lantigua Rafael, Medrano Martin, Rivera Diones, Honig Lawrence S, Mayeux Richard, Miller Gary W, Vardarajan Badri N
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University. 722 West 168 Street, New York, NY 10032.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University. 630 West 168 Street, New York, NY 10032.
medRxiv. 2023 Aug 25:2023.08.24.23294581. doi: 10.1101/2023.08.24.23294581.
We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.
We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels.
Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an ε (OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least one ε allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aβ42/Aβ40 ratio reflecting different pathways enriched in early and middle stages of disease.
Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed an ε dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.
我们通过研究循环血浆代谢物与阿尔茨海默病（AD）的临床诊断及生物标志物辅助诊断之间的关系，来探究AD患者的全身生化变化。
我们采用非靶向方法，将液相色谱与高分辨率质谱联用，以测量150例临床诊断为AD的个体以及567例年龄匹配的无痴呆症的加勒比西班牙裔老年人血浆中的外源性和内源性小分子代谢物。还测量了AD的血浆生物标志物，包括磷酸化tau蛋白181（P-tau181）、淀粉样β蛋白40（Aβ40）、淀粉样β蛋白42（Aβ42）、总tau蛋白、神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP）。对代谢物的个体模块和共表达模块与AD的临床诊断以及基于P-tau181和其他生物标志物水平的生物学定义的AD病理过程进行了关联测试。
精确测量了4000多个代谢组学特征。与二十二碳六烯酸（DHA）、二十碳五烯酸（EPA）和花生四烯酸（AHA）结合或相互作用的溶血磷脂酰胆碱（lysoPC）的第一主成分（PC）与AD风险降低相关（OR = 0.91 [0.89 - 0.96]，p = 2×10⁻⁴）。在没有ε4等位基因的个体中（OR = 0.89 [0.84 - 0.94]，p = 8.7×10⁻⁵），这种关联仍然存在。在携带至少一个ε4等位基因的个体中，lysoPCs的PC4适度增加了AD风险（OR = 1.37 [1.16 - 1.6]，p = 1×10⁻⁴）。包括酪氨酸代谢途径在内的必需氨基酸在与P-tau181水平相关的代谢物中富集，硫酸乙酰肝素和硫酸角质素降解途径与反映疾病早期和中期富集的不同途径的Aβ42/Aβ40比值相关。
我们的研究结果表明，无偏代谢谱分析可以识别与β-淀粉样蛋白和磷酸化tau病理相关的关键代谢物和途径。我们还观察到lysoPCs与AD存在ε4依赖性关联，并且基于生物学的诊断标准可能有助于识别独特的致病机制。
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