Wang C, Yang C, Western D, Ali M, Wang Y, Phuah CL, Budde J, Wang L, Gorijala P, Timsina J, Ruiz A, Pastor P, Fernandez MV, Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Disease Neuroimaging Initiative (ADNI), Panyard DJ, Engelman CD, Deming Y, Boada M, Cano A, Garcia-Gonzalez P, Graff-Radford NR, Mori H, Lee JH, Perrin RJ, Ibanez L, Sung YJ, Cruchaga C. Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits. Nat Genet. 2024 Dec;56(12):2685-2695. Epub 2024 Nov 11 PubMed.
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King’s College London/Steno Diabetes Center Copenhagen
This gene-to-molecule research is crucial for discovery in Alzheimer’s disease, offering fresh perspectives on how genetic risk factors, such as APOE, influence metabolism and perhaps disease progression.
The association between APOE and glycerophospholipids in CSF is particularly intriguing, especially in the context of the unsaturated fatty acids attached to phosphatidylcholines reported in the paper. We have shown in human participants that most fatty acid levels in the brain decrease in Alzheimer’s disease (Whiley et al., 2014), and that particular PCs in the blood are also reduced at asymptomatic stage (Snowden et al., 2017). Others have shown that in animal models the 14:0 myristic acid is key to memory formation (Akefe et al., 2024). Understanding the interplay between genetics and lipids in Alzheimer’s and finding ways to achieve "lipid repair" is an exciting area of research.
Studying omics for metabolism is totally dependent in advances in technology. Each lab develops its own methods and is trying for the most precise measurements of thousands of molecules. The wide range of concentrations of molecules makes this a challenge but also an opportunity for discovery.
View all comments by Cristina Legido QuigleyMedical University of Graz / Division Medicinal Chemistry
This publication presents a comprehensive genome-wide association study on brain and CSF metabolite levels, and reveals significant metabolic changes associated with various diseases, including Alzheimer’s. The authors have also developed a webserver that allows further exploration of their data on metabolite genome-wide association studies and related molecular traits, providing a valuable resource for the research community.
Wang et al. combined several datasets of brain metabolites collected from samples of the parietal lobe cortex, dorsolateral prefrontal cortex, and temporal cortex. However, since metabolite profiles can vary significantly between different brain regions, this approach might introduce biases related to the distribution of sample sizes across these areas. Furthermore, by merging datasets that exhibit regional variations in metabolite levels, potentially important changes could be obscured. For example, our study highlighted notable differences in the levels of several amino acids, lactate, taurine, and creatine across the cerebellum, frontal, and occipital cortices (Zhang et al., 2023). It would be interesting for future studies to consider analyzing metabolite profiles from individual brain regions to pinpoint more specific changes. It would also be beneficial to determine which brain tissues most closely reflect CSF metabolite levels.
One finding from Wang et al. that I found most exciting is the association of the APOE locus with multiple CSF glycerophosphocholines (GPCs) and its co-localization with several conditions, including Type 2 diabetes, Alzheimer’s disease, frontotemporal dementia (FTD), and cognitive performance. This aligns with our previous findings, which indicated an increase in the catabolic metabolite glycerophosphocholine—a breakdown product of glycerophospholipids—in FTD and Alzheimer's disease compared to controls. This has been further corroborated by studies that have shown that glycerophosphocholine levels are elevated in both the CSF and blood of Alzheimer’s patients (Jia et al., 2021; Walter et al., 2004). Glycerophosphocholine, involved in both the synthesis and degradation of cell membranes, reflects changes in the structural integrity of neural cells (Klein 2000).
Wang et al. not only advances our understanding of the genetic factors influencing metabolite levels in the brain and CSF but also reinforces the role of the APOE locus in neurodegenerative diseases, such as Alzheimer's. It underscores the complexity of metabolite variations across different brain regions and their implications for disease mechanisms. Future research should focus on dissecting these regional differences more deeply and correlating them with CSF metabolite profiles to enhance our understanding of the underlying pathology.
References:
Jia L, Yang J, Zhu M, Pang Y, Wang Q, Wei Q, Li Y, Li T, Li F, Wang Q, Li Y, Wei Y. A metabolite panel that differentiates Alzheimer's disease from other dementia types. Alzheimers Dement. 2021 Nov 17; PubMed.
Klein J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J Neural Transm (Vienna). 2000;107(8-9):1027-63. PubMed.
Walter A, Korth U, Hilgert M, Hartmann J, Weichel O, Fassbender K, Schmitt A, Klein J. Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients. Neurobiol Aging. 2004 Nov-Dec;25(10):1299-303. PubMed.
Zhang F, Rakhimbekova A, Lashley T, Madl T. Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease. Prog Neurobiol. 2023 Feb;221:102400. Epub 2022 Dec 26 PubMed.
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