# Association between Large Neutral Amino Acids and Brain Integrity in Middle-Aged Adults at Metabolic Risk

## TL;DR

This study explores how large neutral amino acids and metabolic syndrome may affect brain structure and cognitive health in middle-aged adults.

## Contribution

The study reveals a potential link between elevated phenylalanine levels and brain structural changes in individuals with metabolic syndrome.

## Key findings

- Phenylalanine levels moderate the relationship between metabolic syndrome and white matter hyperintensity volume.
- LNAA metabolites do not significantly affect medial temporal lobe cortical thickness in relation to metabolic syndrome.
- Elevated LNAA levels in metabolic syndrome may correlate with brain structural compromises detectable in midlife.

## Abstract

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure and cognitive function. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, our study hypothesizes a reversal of these benefits in older adults with MetS, potentially signaling premature cognitive aging. Eighty participants between 40–61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensity (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analysis, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting that MetS’s cognitive impact may be partly due to phenylalanine catabolism byproducts. However, LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. The findings suggest that LNAA metabolic dysregulation, marked by elevated levels in the presence of MetS, could correlate with brain structural compromises, particularly in the form of MTL cortical thinning and increased WMH load, detectable in midlife. This nuanced understanding of LNAA’s role in cognitive health amid cardiovascular risk factors is pivotal, proposing a potential biomarker for early intervention. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.