Associations between Elevated Circulating Amino Acid Levels and Brain Health: A Mendelian Randomization Study in the UK Biobank

Background: previous research has demonstrated a relationship between chronically elevated postabsorptive amino acid (AA) levels and the pathophysiology of neurological disorders such as dementia. It is unclear if some of these associations are causal or secondary to other pathologies. Amino acid metabolism also has a complex relationship with glycaemia, which itself may be implicated in brain health and the aetiology of dementia. Study design: we implemented a two-sample Mendelian randomisation (MR) in the UK Biobank (maximum N=375,078 participants) utilising exposure data from a recent genome-wide association study (GWAS) of circulating metabolites. Both univariate and multivariable MR methods were implemented, complemented by standard sensitivity analyses using the weighted median estimator, Egger regression, and MR-PRESSO. Our exposures were genetic instruments proxying elevated levels of the branched chain AAs (BCAAs; isoleucine, leucine, and valine), aromatic AAs (AAAs; phenylalanine, tyrosine, and histidine), and glycated haemoglobin A1c (HbA1c). Our outcomes were subcortical volume measures (of the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus); total brain and white matter hyperintensity (WMH) volumes; and all-cause dementia (ACD), vascular dementia (VaD), and Alzheimer's dementia (AD). Results: we found evidence of direct associations independent of glycaemia between genetically-proxied elevated circulating tyrosine and multiple subcortical volumes of the accumbens ( {beta} = 11.0 95%CI [4.2, 17.8] mm3 / mmol L-1), caudate ({beta} = 30 95% CI [2.9, 5.71] mm3 / mmol L-1), hippocampus ({beta} = 43.1 95%CI [14.1, 72.1] mm3 / mmol L-1), and thalamus ({beta}= 81.4 95%CI [8.54, 154.3] mm3 / mmol L-1). For dementia outcomes, elevated valine and histidine were associated with a reduced (OR = 0.45 95% CI [0.21, 0.96] / mmol L-1) and increased (OR = 1.47 95% CI [1.03, 2.09] / mmol L-1) vascular dementia risk, respectively. Conclusions: elevated circulating tyrosine was associated with increases in several subcortical volumes, and these effects were found to be independent of glycaemia. This warrants further investigation as to the effects and possible benefits of tyrosine modification or supplementation in the diet to protect against brain atrophy and the development of neurological disorders. On the other hand, associations between circulating AAs and vascular dementia may indicate mechanistic effects of chronically elevated AA levels on dementia.