Shedding new light on metabolism, Alzheimer’s pathology and cognitive decline

Lausanne, Switzerland 21st June 2017. High levels of homocysteine (Hcy), an amino acid and metabolite of the methionine pathway, is a known risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD).

Elevated plasma Hcy can be attributed to insufficient intake of food or supplement derived B vitamins, although consuming Hcy-lowering B vitamins (B6, B9, B12) has not been proven to prevent cognitive decline or the progression of Alzheimer’s disease.  In collaboration with the research group lead by Julius Popp from the CHUV  (Centre Hospitalier Universitaire Vaudois), NIHS researchers investigated the interrelated methionine, purine and thymidylate cycles, which constitute the so called ‘One-Carbon Metabolism’, and play a central role in cellular metabolism and risk of metabolic, cardiovascular and neurodegenerative diseases, as well as cancer1.

A metabolomic approach was used to target the one-carbon pathway more comprehensively and test the hypothesis that disturbances in this pathway beyond Hcy are relevant to cognitive function and the underlying pathological hallmarks of beta-amyloid and hyperphosphorylated tau proteins in the cerebral spinal fluid (CSF) of older adults. The results of this new study are published in the medical journal Alzheimer’s Research & Therapy2.

We know that one-carbon metabolism can govern epigenetic maintenance and a multitude of physiological processes in humans.  The researchers analysed CSF and plasma samples collected from 120 older adults with or without cognitive impairment, deploying a new mass spectrometry-based assay that enables them to quantify one-carbon metabolites and their cofactors more comprehensively3.

"Our results show that several one-carbon metabolites beyond Hcy in the periphery are associated with cognitive impairment in older adults, such as methionine, serine, choline and cysteine", explains Loïc Dayon, who is lead author of the article.  “We achieved this by leveraging techniques developed in-house to analyse the full range of metabolites in the one-carbon metabolism and provide a comprehensive view of this important pathway.  Most research laboratories have only reported on a single or limited number of metabolites in the pathway.”

One intriguing finding was that these metabolites appear more critical in individuals carrying the ApoE ε4 allele, a major genetic risk loci for late onset or sporadic Alzheimer’s disease.

“This study confirms that disturbances in one-carbon metabolism are relevant to cognition, but in a way not previously thought. Regardless of the metabolite, the entire pathway appears to influence tau metabolism more profoundly than amyloid mechanisms. This could explain why previous homocysteine-lowering trials have been mostly disappointing”, adds Gene Bowman, Head of Nutrition and Brain Health at NIHS.

“Once we (or others) confirm these results, then nutritional interventions can be formulated to target these alternative aspects of one-carbon metabolism in the hope of preventing age-related dementia, including Alzheimer’s disease.”

 

About NIHS:

NIHS is a biomedical research institute, part of Nestlé’s global R&D network, dedicated to fundamental research aimed at understanding health and disease and developing science-based, targeted nutritional solutions for the maintenance of health. To achieve its aim, NIHS employs state-of-the-art technologies and biological models to characterise health and disease with a holistic and integrated approach. The ultimate goal of the Institute is to develop knowledge that can empower people to better maintain their health through nutritional approaches, especially in relation to their molecular profile and lifestyle status.


References:

1. Vauzour, D., Camprubi-Robles, M., Miquel-Kergoat, S., Andres-Lacueva, C., Bánáti, D., Barberger-Gateau, P., Bowman, GL., Caberlotto, L., Clarke, R., Hogervorst, E., Kiliaan, AJ., Lucca, U., Manach, C., Minihane, AM., Mitchell, ES., Perneczky, R., Perry, H., Roussel, AM., Schuermans, J,. Sijben, J., Spencer, JP., Thuret, S., van de Rest, O., Vandewoude, M., Wesnes, K., Williams, RJ., Williams, RS., Ramirez, M. Nutrition for the ageing brain: Towards evidence for an optimal diet. Ageing Res Rev. 2017;35:222-240.

2. Dayon, L., Guiraud, SP., Corthésy, J., Da Silva, L., Migliavacca, E., Tautvydaitė, D., Oikonomidi, A., Moullet, B., Henry, H., Métairon, S., Marquis, J., Descombes, P., Collino, S.,  Martin, FPJ., Montoliu, I., Kussmann, M., Wojcik, J., Bowman, GL., and Popp, J. One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. Alzheimers Res Ther. 2017;9:43.

3. Guiraud, SP., Montoliu, I., Da Silva, L., Dayon, L., Núñez Galindo, A., Corthésy, J., Kussmann, M., and Martin, FP. High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS/MS. Anal Bioanal Chem. 2017; 409:295-305.

This study received support from the Swiss National Research grant FNS 320030_141179 to J. Popp.

For enquiries, please contact:

Laura Camurri, Communications, NIHS

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