Tynkkynen et al. Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer’s disease: A prospective study in eight cohorts. Alzheimer’s & Dementia. 2018;1-11. March 6, 2018.
It’s estimated that 47 million people worldwide suffer from dementia, with this number projected to triple by 2050. In order to manage the significant burden that neurodegenerative diseases pose for society and national healthcare systems, there is a demand for effective diagnostic techniques to facilitate early detection, accurate risk prediction and the development of therapeutic interventions.
To bring about preventive care for dementia, it’s essential that we unravel the pathophysiology causes of neurodegenerative diseases. Decades of animal model research and clinical trials have so far failed to yield effective prevention or disease-modifying therapies for late-onset clinical dementia and Alzheimer’s disease. Metabolomics analysis of blood metabolites therefore offer a new approach towards identifying new metabolites for risk prediction. With the advent of high-throughput metabolomics, there is now significant interest in the contributions metabolomics can provide to neurodegenerative disease research – especially as metabolites reflect genetic and environmental factors, readily cross the blood-brain barrier, and are modifiable through medication and lifestyle interventions.
In a large prospective study of 22,623 participants, Tynkkynen and colleagues used Nightingale’s high-throughput NMR assay to measure 228 circulating metabolites in seven (out of eight) cohorts analysed. All study participants were free of dementia at baseline, with 995 incident dementia and 745 Alzheimer’s disease cases observed across the cohorts. Overall, 10 biomarkers (metabolites or lipid measures) were found to be associated with the risk for developing dementia. Of these, lower blood concentrations of branched chain amino acids (isoleucine, leucine and valine) were associated with increased risk of dementia and Alzheimer’s disease. Also, low concentrations of blood creatinine, total cholesterol in small very low-density lipoprotein cholesterol (S-VLDL-C), and triglycerides to total lipids ration in very large VLDL, were found to associate with the risk for developing dementia after the blood sampling. In addition, higher concentration of cholesterol esters relative to total lipids in large high-density lipoproteins (HDL) and total cholesterol to total lipids ratio in very large VLDL were found to predict increased dementia risk.
Pronounced decline in cognitive performance is a key feature characterizing all neurodegenerative diseases, with clinical and epidemiological evidence suggesting a relationship between cognitive function and a number of metabolic aberrations. Associations of low blood concentrations of branched chain amino acids have not been previously reported for the risk of dementia. The findings may possibly indicate that weight loss and dietary intake may play a role in dementia risk, pointing to branched chain amino acid levels as important early markers of mild cognitive impairment. This runs counter to previous studies that have consistently shown that elevated levels of branched chain amino acids are reflective of insulin resistance and type 2 diabetes risk – however the results in the present study in relation to dementia was observed as being consistent across all eight of the cohorts analysed.
Further studies investigating branched chain amino acids could lead to further replication of these associations, assessment of causality and more effective assessment of neurodegenerative disease risk. Nightingale’s high-throughput metabolomics assay also offers the potential for dynamic readouts of the molecular effects resulting from preventative lifestyle changes or therapeutic interventions, facilitating targeted treatment of the molecular mechanisms that underpin dementia.
This study is an example of Nightingale's NMR metabolomics platform being applied in neurodegenerative disease research, as part of a joint research project coordinated by the National Institute for Health and Welfare Finland (THL), the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases and the Framingham Heart Study. Our blood analysis service can be utilized to investigate the molecular mechanisms underpinning dementia, using metabolic profiling to identify circulating biomarkers associated with cognitive function and neurodegenerative diseases.
In this study, our assay was used to quantify metabolic measures (including detailed lipid and lipoprotein particle profiles), for 20,452 participants across four discovery cohorts, with results being further replicated in four independent cohorts (N total= 22,623). Nightingale's assay has been successfully used in a wide range of research applications and has featured in over 100 peer-reviewed studies.
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